the cardiovascular physiology of obstetric spinal ... · three clinical investigations together...
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THE INFERIOR VENA CAVAL COMPRESSION THEORY OFHYPOTENSION IN OBSTETRIC SPINAL ANAESTHESIA: STUDIESIN NORMAL AND PREECLAMPTIC PREGNANCY, A LITERATURE
REVIEW AND REVISION OF FUNDAMENTAL CONCEPTS
Geoffrey H. Sharwood-Smith
A Thesis Submitted for the Degree of MDat the
University of St. Andrews
2011
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The following publications are deposited in Research@StAndrews:FullText by permission of
the publishers, as part of the portfolio thesis available at http://hdl.handle.net/10023/1815
Sharwood-Smith, G., Clark, V. and Watson, E. 1999. Regional anaesthesia for caesarean
section in severe preeclampsia: spinal anaesthesia is the preferred choice. International
Journal of Obstetric Anesthesia. 8(2): 85-89. DOI: 10.1016/S0959-289X(99)80003-X
Copyright ©1999 Elsevier Ltd.
Clark, V.A., Sharwood-Smith, G.H. and Stewart, A.V.G. 2005. Ephedrine requirements are
reduced during spinal anaesthesia for caesarean section in preeclampsia. International
Journal of Obstetric Anesthesia. 14(1): 9-13. DOI: 10.1016/j.ijoa.2004.08.002 Copyright
©2004 Elsevier Ltd.
Bruce, J., Sharwood-Smith, G. and Drummond, G. 2002. Pulse transit time: a new approach
to haemodynamic monitoring in obstetric spinal anaesthesia. International Journal of
Obstetric Anesthesia. 11, Supplement 1: 6. Copyright ©2002 Elsevier Ltd.
Sharwood-Smith, G., Drummond, G. and Bruce, J. 2002. Pulse transit time confirms altered
haemodynamic response to spinal anaesthesia in pregnancy induced hypertension.
Hypertension in Pregnancy. 21, Supplement 1: 31. Published version © Informa Healthcare
Sharwood-Smith, G., Drummond, G. and Bruce, J. 2002. Pulse transit time confirms altered
response to spinal anaesthesia in pregnancy induced hypertension [Poster]. International
Society for the Study of Hypertension in Pregnancy (ISSHP) Congress, Toronto 2002. © The
authors
Sharwood-Smith, G., Bruce, J. and Drummond, G. 2006. Assessment of pulse transit time to
indicate cardiovascular changes during obstetric spinal anaesthesia. British Journal of
Anaesthesia. 96(1): 100-105. DOI: 10.1093/bja/aei266 © The Board of Management and
Trustees of the British Journal of Anaesthesia 2005.
Sharwood-Smith, G. and Drummond, G.B. 2009. Hypotension in obstetric spinal
anaesthesia: a lesson from pre-eclampsia. British Journal of Anaesthesia. 102(3): 291-294.
DOI: 10.1093/bja/aep003 © The Board of Management and Trustees of the British Journal
of Anaesthesia 2009.
The inferior vena caval compression theory of hypotension in obstetric spinal
anaesthesia: studies in normal and preeclamptic pregnancy, a literature review
and revision of fundamental concepts
Thesis Submission to the University of St Andrews for the Degree of Doctor of Medicine 2011.
Geoffrey H Sharwood-Smith
© G H Sharwood-Smith 2011 All Rights Reserved
2
The inferior vena caval compression theory of hypotension in obstetric spinal
anaesthesia: studies in normal and preeclamptic pregnancy, a literature review
and revision of fundamental concepts
Dr G H Sharwood-Smith MB ChB (St And.) DA FRCA 37 Thorburn Road, Edinburgh EH13 0BH
Current Position:
Part Time Clinical Teaching Staff (Director of Studies),
Medical School, University of Edinburgh EH16 4HA
Previously:
1986 - 2008:
Consultant Obstetric Anaesthetist,
Department of Anaesthesia, Royal Infirmary, Edinburgh EH16 4HA
3
CONTENTS
ABSTRACT.......................................................................................................................................................4
APPRAISALS
1. Spinal versus epidural anaesthesia in severe preeclampsia......................................................................5
2. Spinal anaesthesia in severe preeclampsia versus normal pregnancy....................................................13
3. The use of pulse transit time to assess cardiovascular changes in spinal anaesthesia: preeclampsia
versus normal pregnancy........................................................................................................................17
4. A reappraisal of the concept of hypotension following obstetric spinal anaesthesia: an editorial and
literature review......................................................................................................................................23
Conclusion.............................................................................................................................................39
RESEARCH CONTRIBUTIONS..................................................................................................................42
ACKNOWLEDGEMENTS............................................................................................................................43
COMPETING INTERESTS..........................................................................................................................44
REFERENCES................................................................................................................................................45
THESIS ALGORITHM..................................................................................................................................52
PUBLICATIONS (numbered as ‘Thesis page’)
Sharwood-Smith G, Clark V Watson E. Regional anaesthesia for caesarean section in severe
preeclampsia: spinal anaesthesia is the preferred choice. Int J Obstet Anaesth 1999; 8: 85-9.............. 53
Clark V A, Sharwood-Smith GH , Stewart AVG. Ephedrine requirements are reduced during spinal
anaesthesia for caesarean section in preeclampsia. Int J Obstet Anesth 2005; 14: 9-13........................58
Bruce J, Sharwood-Smith G, Drummond G. Pulse transit time: a new approach to haemodynamic
monitoring in obstetric spinal anaesthesia. Int J Obstet Anaesth 2002; 11, Supplement 1, 1- 38..........63
Sharwood-Smith G, Drummond G, Bruce J. Pulse transit time confirms altered haemodynamic
response to spinal anaesthesia in pregnancy induced hypertension. Hypertension in Pregnancy 2002;
21 suppl 1: 31..........................................................................................................................................64
Sharwood-Smith G, Drummond G, Bruce J. Pulse transit time confirms altered response to spinal
anaesthesia in pregnancy induced hypertension. (poster annex to the above abstract)........................65
Sharwood-Smith G, Bruce J and Drummond G. Assessment of pulse transit time to indicate
cardiovascular changes during obstetric spinal anaesthesia. Br J Anaesth 2006; 96: 100-5..................66
Sharwood-Smith G, Drummond G B. Hypotension in obstetric spinal anaesthesia: a lesson from pre-
eclampsia. Br J Anaesth 2009; 102: 291-4.............................................................................................72
4
ABSTRACT
Three clinical investigations together with a combined editorial and review of the cardiovascular physiology
of spinal anaesthesia in normal and preeclamptic pregnancy form the basis of a thesis to be submitted for the
degree of Doctor of Medicine at the University of St Andrews. First, the longstanding consensus that spinal
anaesthesia could cause severe hypotension in severe preeclampsia was examined using three approaches.
The doses of ephedrine required to maintain systolic blood pressure above predetermined limits were first
compared in spinal versus epidural anaesthesia. The doses of ephedrine required were then similarly studied
during spinal anaesthesia in preeclamptic versus normal control subjects. The principal outcome of these
studies, that preeclamptic patients were resistant to hypotension after a spinal anaesthetic, was then further
investigated by studying pulse transit time (PTT) changes in normal versus preeclamptic pregnancy. PTT
was explored both as beat-to-beat monitor of cardiovascular function and also as an indicator of changes in
arterial stiffness. The cardiovascular physiology of obstetric spinal anaesthesia was then reviewed in the light
of the three clinical investigations, developments in reproductive vascular biology and the regulation of
venous capacitance. It is argued that the theory of a role for vena caval compression as the single cause of
spinal anaesthetic induced hypotension in obstetrics should be revised.
5
APPRAISAL 1
Spinal versus epidural anaesthesia in severe preeclampsia
Linked publication page 53
Sharwood-Smith G, Clark V Watson E. Regional anaesthesia for caesarean section in severe
preeclampsia: spinal anaesthesia is the preferred choice. Int J Obstet Anaesth 1999; 8: 85-9.
Introduction
The first appraisal reviews the first investigation and linked publication; it also compares the study design
and outcomes with the work of other investigators. It introduces the clinical and physiological concepts to be
explored later in the thesis.
Background
Between 1992 and 1994 I led a major review of clinical practice in the management of preeclampsia in the
large tertiary referral obstetric unit at Edinburgh Royal Infirmary. 1 The areas of concern were the anaesthetic
management of preeclamptic patients and the development of multidisciplinary clinical guidelines for use in
the labour ward and obstetric high dependency unit. I identified the increasing use of spinal anaesthesia for
Caesarean section in severe preeclampsia as an area with considerable potential for clinical research.
Pre-eclampsia: general and regional anaesthesia
Preeclampsia is part of a spectrum of pregnancy related hypertensive disorders; it affects 6-8% of all
pregnancies and increases the risk of maternal and foetal morbidity and mortality. Anaesthesia in
preeclampsia similarly carries a relatively increased risk to mother and foetus, a problem that was recognised
some forty years ago. 2
The main anaesthetic issues are related to endotracheal intubation. It can not only be
technically difficult due to airway oedema, but may also cause acute reflex hypertension leading to
eclampsia. The alternative regional anaesthetic techniques, spinal or epidural, have been known to cause
hypotension in normal pregnancy since the 1950’s. However, in preeclampsia, autonomic instability and a
6
relatively reduced plasma volume were more recently thought to contribute to the risk of even more
profound hypotension after regional anaesthesia. 3 Also there was thought to be a risk of pulmonary oedema
resulting from resuscitation attempts with uncontrolled administration of intravenous fluids and vasopressor
drugs. 3, 4
Additionally, it was also suggested that an ‘awake’ mother could become anxious, thus
precipitating hypertension and an eclamptic fit. 3 So there was a physiological ambiguity in interpreting these
cardiovascular responses. For example, in the U.K., there was a perception that epidural anaesthesia for
labour had relatively little effect in reducing blood pressure in preeclampsia; but, in an apparent paradox,
there was also still thought to be a risk of regional anaesthesia causing severe hypotension in Caesarean
section. 2
In North America, by contrast, epidural anaesthesia was increasingly being used for Caesarean
section in preeclampsia. 5
The slower incremental onset of sensory and autonomic blockade with an epidural
was thought to be more controllable and therefore less likely to precipitate hypotension. However, even in
North America, spinal anaesthesia was still not recommended. 6
There were no studies cited in support of
the view that spinal anaesthesia would cause severe hypotension. Clinical practice was therefore based on a
consensus of theoretical considerations and the opinion of leading practitioners in the, still developing,
speciality of obstetric anaesthesia.
Evidence on the use of spinal anaesthesia in preeclampsia
The increasing use of spinal anaesthesia in severe preeclampsia in our unit therefore seemed to go against
this prevailing consensus. However there was recent support in the literature. A retrospective study
comparing spinal versus epidural anaesthesia in severe preeclampsia had been reported in a conference
abstract. Against the consensus, the study suggested that spinals were not more likely to cause hypotension.
The study would subsequently be peer reviewed and published formally. 7, 8
7
Design and Methods
The simple working hypothesis of our first study, in line with contemporary thinking, was that spinal rather
that epidural anaesthesia would be likely to cause hypotension; there would therefore be a consequent
difference in ephedrine requirement to maintain blood pressure between the groups. The patients in the
planned study would satisfy the following criteria: be non-labouring, have severe hypertensive, proteinuric
preeclampsia; further, they would be stabilised on antihypertensive therapy, be scheduled for non-emergency
Caesarean section and be suitable for randomisation to either spinal or epidural anaesthesia. The techniques
used would be in line with the then standard clinical practice required to achieve adequate anaesthesia, i.e. in
terms of the density and segmental height of sensory block for a Caesarean section. In both groups systolic
blood pressure, measured non-invasively, would be maintained at above 70% of the baseline pre anaesthesia
level by the administration of standardised boluses of ephedrine. This protocol followed a standardised
version of normal clinical practice. The mean ephedrine dose required for each group would be compared,
and this would be the primary outcome of the study. Secondary outcomes included gestational ages, adverse
intra-operative events, neonatal Apgar scores and any continuing relevant health problems one month after
delivery. Other than the actual method of anaesthesia all other clinical management including fluid
administration and positioning would be standardised in both groups. It was not possible to blind an observer
because the differences in the two anaesthetic procedures would be readily identified. Strict criteria were
otherwise applied to generate equivalent groups for comparison. Factors such as extremes of height, weight
or incidental complicating medical conditions were excluded so that the standardised anaesthetic technique
could be used appropriately and safely.
Results
Based on a pilot study it had been planned to power the study at 80% to detect a mean difference of 6mg
ephedrine between the two groups. This would have required 40 patients for each arm of the study. However
it quickly became clear that some patients required no ephedrine; more importantly, the spinal was delivering
a significantly superior quality of anaesthesia in terms breakthrough pain and nausea. This posed a difficult
8
question. Was it justified to continue randomising patients so that some would receive what appeared to be
an inferior technique? Importantly, there was recent evidence to suggest that epidural analgesia could be
improved by the addition of an opioid. 9
Although a logical step in these circumstances, it was not our unit
clinical practice to add an opioid to the spinal. This change in the protocol i.e. only using an opioid in the
epidurals therefore created an element of non standardisation between the two groups, although it was
probably clinically unimportant. However, despite the alteration to the technique, the epidural group
continued to experience relatively poor anaesthesia. After some consideration, the ethics committee
recommended that the study be concluded and the results reported after randomising a total of 28 patients.
There was no significant difference in the mean ephedrine doses between the groups (5.2 mg in the spinal
and 6.3 mg in the epidural group) and the neonatal Apgar scores were also similar.
Discussion
Defining pre-eclampsia
The main problem for any study on anaesthesia in preeclampsia was, and remains, one of semantics and
classification. Preeclampsia is a heterogeneous condition typically characterised by hypertension developing
after the twentieth week of gestation with proteinuria. Various attempts have been made to classify
preeclampsia, for example by using categories like mild, moderate and severe. A widely accepted
classification defined certain minimum systolic and diastolic pressure limits. 10
Proteinuria was specified in
terms of method of measurement and mass of protein excreted over 24 hours. Despite imposing such
demanding criteria, the authors conceded that the causes of hypertension in pregnancy were largely unknown
at the time. Severe preeclampsia, at various times in its development, can include hepatic, renal,
haematological and cerebrovascular pathologies alone or in combination. Hypertension as a consequence of
peripheral vascular endothelial pathology appeared to be the critical factor leading to the concerns that
arterial pressure would be labile if of spinal anaesthesia was used. Therefore the presentation of ‘severe’
hypertension developing after the twentieth week of gestation was selected as the main criterion for
including patients in our studies. Proteinuria, as strictly defined, was thought at the time to be a requirement
9
for the category ‘severe preeclampsia’. However it was becoming clear that proteinuria can be latent and
develop at any stage during the disease i.e. up to or after the point of delivery. It was, and is, also often
difficult to measure reliably in a labour ward setting. 11
The differentiation of patients into ‘pre-eclampsia’ -
hypertension with proteinuria, or ‘pregnancy induced hypertension (PIH) - hypertension without proteinuria,
appeared to represent different pathologies. Therefore there could be ‘PIH’, with varying degrees of
proteinuria, or alternatively ‘preeclampsia’ with proteinuria, but only as specified. The heterogeneous
nature of preeclampsia continues to challenge attempts to classify the pathology. 12
For this first study the classical presentation of severe preeclampsia as ‘severe hypertension and proteinuria
‘as defined’ was adopted. 10
Other studies
In the single relevant previous publication already mentioned, Hood et al had retrospectively compared blood
pressure changes and ephedrine doses between two groups: 103 women who had received spinals for
Caesarean section and 35 who had been given epidural anaesthesia. 8
This study was useful and informative
although physiological data and case selection were determined retrospectively
Fortuitously, when our proposed study was under consideration by the unit ethics committee, a second, but
this time prospective, study was published by Wallace et al. 13
This study was a three way comparison
between general, epidural and combined spinal epidural anaesthesia in severe preeclampsia. It was not
therefore a direct comparison of spinal and epidural anaesthesia. Their approach was very different from that
of our protocol. The inclusion criteria were relatively complex and standardisation of anaesthetic procedures
was not attempted. Only non emergency cases were studied, however some had been labouring and had
therefore received varying doses of oxytocic therapy. Their subjects had various degrees of proteinuria but
nevertheless, for the purpose of the study, were classified as ‘preeclampsia’. All patients had been given
intramuscular magnesium sulphate, an eclampsia prophylactic and hypotensive agent. Rather than a period
of blood pressure stabilisation on oral therapy they had been given intermittent ad hoc intravenous
hydralazine boluses. The general anaesthetic group received relatively larger intravenous fluid volumes. The
primary outcome was the mean arterial pressure of each group derived from non invasive blood pressure
10
measurements at various key times during the procedures. Secondary outcomes included intravenous fluid
volumes administered and the recorded neonatal condition. The latter was assessed by Apgar scores,
umbilical artery blood gases, birth weight and gestational age. Ephedrine doses were not reported, only the
number of subjects in each group that actually received ephedrine. There were no significant differences
between the groups in terms of mean blood pressure at key moments or in the secondary outcomes. The
statistical power analysis suggested that the secondary outcomes of ’no differences’ between the groups
could include a type 2 error. The primary outcome did not appear to have been powered.
In more recent study Visalyaputra (2005) used another approach with a larger multicentre design comparing
spinal versus epidural anaesthesia. 14
A total of 120 severely preeclamptic subjects were studied in five
centres. The investigators noted that mean arterial pressure was frequently measured (every 2 minutes) to
monitor hypotension although ephedrine was administered on the basis of systolic readings – raising the
concerns on diastolic pressure estimation discussed below. 91% of both groups received magnesium sulphate
and 34% and of epidural and 39% of spinal groups were given intravenous hydralazine according to their
protocol. There were varying numbers of twins and triplets delivered in each group. Pre-anaesthetic and
intraoperative fluid volume ranges indicated difficulty in controlling these elements of clinical management.
However the large number of subjects studied gave some statistical reliability to the principal outcome which
supported the use of spinal anaesthesia in severe preeclampsia.
This study
The main advantages compared to the other studies were of clarity and simplicity; the two anaesthetic
techniques, spinal and epidural anaesthesia, were directly compared. Confounding variables were reduced to
the minimum that was clinically possible. The principal outcome, the intravenous ephedrine requirement to
maintain systolic blood pressure above a defined level, was simple to record accurately for comparison
between the groups.
The main disadvantages were that the numbers studied were relatively small, and we too could not exclude a
type 2 statistical error; in other words there might in fact be a difference between the groups but we could not
demonstrate it. However it can reasonably be argued that the decision, on ethical grounds, i.e. to complete
11
the study after 24 randomisations due the relatively poor anaesthesia of the epidural technique was of
considerable clinical significance. Blood pressure trends were recorded as required for clinical monitoring.
Although, with hindsight, additional blood pressure data would have been desirable, it would not however
have affected the principal outcome of the study. In practice there are also there are reservations on the
fidelity of non invasive of blood pressure diastolic pressure recording and therefore the derived value of
mean arterial pressure. This is discussed and referenced in the linked article. The ‘gold standard’ of intra-
arterial blood pressure monitoring was considered too invasive, and therefore unethical, unless specifically
indicated for an unstable patient. Non invasive blood pressure (NIBP) recordings are difficult to track
frequently and reliably in obstetrics due to patient movement and obesity and this issue is dealt with in detail
in the third study
Implications
Our first study added to evidence suggesting that, far from creating hemodynamic instability, severe
preeclampsia might exert a relatively protective effect, reducing the risk of hypotension. 36% of spinal and
50% of epidural subjects required ephedrine, in a relatively low dose, to maintain systolic blood pressure.
This compared to the higher dose of ephedrine by then known to be required in 80% of normal pregnant
women. These findings had been precisely predicted by the small but elegant studies of Assali more than
forty years before. 15
He had found that normal pregnant compared to non pregnant women demonstrated a
greatly increased sensitivity to hypotension after spinal anaesthesia; contrastingly the presence of severe
hypertensive preeclampsia was associated with resistance to hypotension. The administration of an
autonomic ganglion blocking drug had produced a similar result in a previous study. All subjects were
studied in the supine position. These studies had been effectively lost to the emerging speciality of obstetric
anaesthesia in the 1960’s. In consequence the alternative ‘single cause’ theory of hypotension in obstetric
spinals has dominated anaesthetic textbooks and teaching for more than forty years. 16, 17
In this theory the
gravid uterus was said to trap blood in the legs by compression of the inferior vena cava when the mother is
in the supine position.
12
Further research, at this time, was planned as follows: a study on the apparent effect of preeclampsia in
protecting against spinal induced hypotension would form the basis of a follow up investigation; then, any
further investigations required and a detailed review of the physiology of obstetric spinal anaesthesia would
be planned and undertaken to complete the series.
Publication and Impact of Research
This first study was presented at the Obstetric Anaesthetists Association conference in 1998 and
subsequently published the following year. Recent selected references indicate the impact of this study on
changes in obstetric anaesthetic practice and education. 18, 19, 20
13
APPRAISAL 2
Spinal anaesthesia in severe preeclampsia versus normal pregnancy
Linked publication page 58
Clark VA, Sharwood-Smith GH, Stewart AVG. Ephedrine requirements are reduced during spinal
anaesthesia for caesarean section in preeclampsia. Int J Obstet Anesth 2005; 14: 9-13
Introduction
The idea for this study emerged from the earlier practice review, the first investigation and other published
articles. It seemed, in line with Assali’s studies, 15
that preeclampsia might actually exert a protective effect
on the hypotension caused by sympathetic blockade with a spinal anaesthetic. If demonstrated in a study,
this blood pressure stabilising effect would contrast with the profound hypotension, when untreated, seen
after a spinal in normal pregnancy. The idea for this further study was clearly stated in the discussion section
of the first publication.
Methods
This was a cohort study design. In other respects the methods used in the previous study were generally
repeated to maintain consistency; anaesthetic and intravenous fluid administration were standardised, the
preeclamptic patients were non-labouring, suitable for spinal anaesthesia and had already been stabilised
haemodynamically. However we did amend the anaesthetic protocol in accordance with changes in our
unit’s clinical practice. Tighter blood pressure control meant that the trigger for ephedrine bolus
administration was a reduction in systolic blood pressure to below 80 %, rather than 70% of the baseline
recording. As previously mentioned, there was evidence that the addition of an opioid improved the quality
of spinal and epidural anaesthesia; fentanyl was therefore added to the local anaesthetic. 9 Based on
published investigations, the study was powered at 90% to show a significant difference of 11 mg in
ephedrine requirement between the groups.
14
Results
In the primary outcome the mean ephedrine requirement of the normal pregnant patients (27.9 ± 11.6 mg)
was significantly greater than that of the pre-eclamptic group (16.4 ± 15 mg) (P<0.01). As an index of
haemodynamic stability, the difference in ephedrine requirement suggested that preeclampsia exerted a
protective effect, reducing the risk of hypotension.
Discussion
Foetal weight and vena caval compression
Was the reduced ephedrine requirement of the pre-eclamptic group simply a matter of foetal ‘weight’?
Earlier gestation at delivery and foetal growth retardation are features of preeclampsia. A smaller foetus
could theoretically cause less vena caval compression and therefore less hypotension during the spinal
anaesthetic. The question had already been partly addressed in one study; resistance to ‘supine hypotension’
due to ‘vena caval compression’ had been demonstrated in a study of 128 non anaesthetised pre-eclamptic
patients. 21
Later, in a more definitive study, 22
Aya et al were to investigate a preterm but otherwise normal
control group and compare them to a preeclamptic group; the result again would suggest that the critical
difference is related to the presence of preeclampsia, not foetal weight..
NIBP measurement
As already mentioned, NIBP measurements suitable for detailed analysis are inherently difficult to obtain.
Consistently reliable and frequent readings are disturbed by patient movement. Diastole pressure and thus the
derived function of mean arterial pressure are not always reliably identified, 23
and haemodynamic changes
can be too rapid for the monitor to track. The gold standard of continuous intra-arterial blood pressure
monitoring was considered to be too invasive for use in the majority of patients. This issue of beat-to-beat
cardiovascular monitoring is difficult and was to be addressed specifically in our third study. In this third
study, the subject of Appraisal 3, additional resources meant that continuous pulse pressure transit time data
were available and non invasive blood pressure recordings could be made at 2 minute intervals. Although not
15
a primary outcome of the study, the arterial pressure trends of the two groups closely followed predictions
from the first two studies. Reservations on diastolic pressure measurement fidelity remain however, and this
is stated in the third publication.
Non-stabilised preeclampsia
Our two studies concerned women with stabilised hypertensive preeclampsia. Because of limited worldwide
resources for antenatal care it is sometimes necessary to anaesthetise unstable preeclamptic patients. It is
important to be clear that our findings could not necessarily be extrapolated to this unstable group.
Competing Publication
The results of a similar research project by Aya et al 24
were published as we revised our own submission in
response to a peer review by the same journal. There were very similar inclusion criteria in the competing
article and the primary outcome was also the dose of ephedrine needed to maintain blood pressure within
defined limits. However there were considerable differences in clinical practice. Hypertension, usually an
acute condition in preeclampsia, was only treated when there was ‘evidence of end organ damage’. Both
groups were given an intravenous ‘prehydration’ load of 1.5 to 2.0 L. in an attempt to prevent hypotension
after the spinal. Some, but not all, patients received magnesium sulphate, an eclampsia prophylactic and
vascular smooth muscle relaxant. Blood pressure and heart rate changes were recorded following spinal
anaesthesia.
In their study, Aya et al described their proposed physiological basis of both their normal clinical practice
and study results as ‘speculative’. Their discussion was useful in that the uncertainty it communicated gave
me an opportunity explore the fundamental conceptions rooted in the early development of obstetric
anaesthesia. The discussion, in study 1 as published, introduced the ideas which were further developed as
discussion in the second publication. This issue is elaborated yet further in the editorial and review in
Appraisal 4. In brief, there was no need to speculate. Critical published evidence supporting a physiological
explanation for the differences in response to spinal anaesthesia in preeclamptic compared to otherwise
normal pregnancy was already available. Cardiovascular changes in early normal pregnancy results in a
generalised vasodilatory state with decreased responses to endogenous and exogenous pressor agents. 25
16
Animal and human work had demonstrated the normal sequence of these cardiovascular changes in
pregnancy. 26, 27
There is a compensatory increase in renin-aldosterone-angiotensin activity which restores
the blood volume. Widespread vascular endothelial damage in pre-eclampsia leads to a failure of this normal
vasodilatory response; hypertension may develop with an increased sensitivity to vasopressors and a relative
hypovolaemia. 28
Subsequently, more extensive damage to the endothelial mechanism may further increase
arterial pressure. Increased excitability or sensitivity to sympathomimetic agents in pre-eclampsia, a
hypertensive state, does not necessarily indicate an increased underlying sympathetic neurogenic tone. There
is evidence of increased sympathetic basal neuronal activity but, critically, it occurs in normal, not pre-
eclamptic pregnancy. This was first demonstrated in animal work and appears to be required for the
maintenance of arterial pressure and to prevent orthostatic hypotension. 29
Therefore when a spinal
anaesthetic is given in normal pregnancy there is usually a profound hypotensive response, unless treated. 30
The relative part played by aortic and vena caval compression in causing hypotension, a core concept in this
thesis, is discussed in Appraisal 4.
A further issue and a difference in our unit’s clinical practice compared was the use of intravenous fluid in a
so called prehydration, load. ‘Prehydration’ in non pre-eclamptic subjects had already been found to be
relatively ineffective in maintaining blood pressure after spinal anaesthesia. 31
Attempts, on theoretical
grounds, to forcibly hydrate, or prehydrate, a severely preeclamptic patient carries the risk of pulmonary
oedema, a problem that developed when non pregnancy related critical care physiology was applied to pre-
eclamptic patients. 4
This was an important concern in the triennial Confidential Enquiry in Maternal Deaths
at the time. 32
Publication and Impact of research
The second study was presented as an abstract in 2001 and published after some delay in January 2005.
Together with our first study the article is cited, among others, in the relevant Cochrane database review The
recent impact is linked to that of study 1 and was discussed and referenced in Appraisal 1.
17
APPRAISAL 3
The use of pulse transit time to assess cardiovascular changes in spinal anaesthesia: preeclampsia
versus normal pregnancy
Linked publications pages 63-71
Bruce J, Sharwood-Smith G, Drummond G. Pulse transit time: a new approach to
haemodynamic monitoring in obstetric spinal anaesthesia. Int J Obstet Anaesth 2002; 11,
Supplement 1, 1-38
Sharwood-Smith G, Drummond G, Bruce J. Pulse transit time confirms altered haemodynamic
response to spinal anaesthesia in pregnancy induced hypertension. Hypertension in Pregnancy
2002; 21 suppl 1: 31
Sharwood-Smith G, Drummond G, Bruce J. Pulse transit time confirms altered response to
spinal anaesthesia in pregnancy induced hypertension. (poster annex to the above abstract).
Sharwood-Smith G, Bruce J and Drummond G. Assessment of pulse transit time to indicate
cardiovascular changes during obstetric spinal anaesthesia. Br J Anaesth 2006; 96: 100-5
Introduction
Outstanding issues in 2000- 2001
There were two outstanding issues at the time. Doubts, expressed editorially, about the stability of severely
pre-eclamptic patients after spinal anaesthesia continued to appear in the literature. 33, 34
Also, improved non
invasive beat to beat cardiovascular monitoring was a desirable requirement for routine use in obstetric
spinal anaesthesia. If such a hypothetical monitoring technique was found to be practicable, it seemed that it
might also have the potential for use in more definitive investigations in normal and pre-eclamptic
pregnancy.
Cardiovascular monitoring
We had already used ephedrine requirements as a surrogate for cardiovascular stability following spinal
anaesthesia. Clinically, heart rate and NIBP were monitored during these studies. While other investigators
had reported and evaluated them we had provided only limited data. However, clinically, it was very
18
important to avoid episodes of maternal hypotension and bradycardia; if prolonged these might reduce
placental perfusion and therefore risk foetal asphyxia. In pre-eclampsia the advantage of accurate
cardiovascular data recording would be that different rates of change, peaks and troughs in cardiovascular
measurements, could be demonstrated. This would still apply, notwithstanding the standardised limits of
systolic blood pressure change that were applied in our studies to determine the requirement for ephedrine
administration. The difficulty, as previously discussed, was the relative unreliability of NIBP diastolic
measurements. A technique that provided a non invasive beat-to-beat index of cardiovascular response to
spinal anaesthesia and quantified arterial wall stiffness could be useful both for physiological research and
also for development as a routine anaesthetic monitor. The significance of arterial stiffness is the issue of
changes in vascular wall physical properties. This amounts firstly to structural changes: the relationship of
vascular compliance to actin-myosin ratio and collagen properties. Animal studies of these structural
vascular changes have utilised large vessels, for practical reasons, although the haemodynamic consequences
appear to be in resistance vessels. 35
Increased vessel stiffness also relates to important functional changes
driven by vascular endothelial cells. 36
In practice, for a study, there were three structural and functional
states to consider: normal vascular function, pregnancy changes and those of preeclampsia. Of various
potential approaches becoming available at the time the measurement of pulse wave velocity seemed to offer
the greatest potential as an investigative tool.
Pulse Wave Velocity (PWV)
PWV is useful because it depends primarily on arterial wall stiffness. PWV increases with ageing due to
increased stiffness of the vascular tree, a principle that was established nearly ninety years ago 37
Measurement of PWV simply requires the recording of two pressure waveform measurements separated by a
known distance. This measurement is the pulse transit time (PTT) which is inversely related to the PWV.
Arterial stiffness can be described in several ways. 38
Compliance, familiar to anaesthetists in pulmonary
physiology, is a volume, diameter or area change for a given pressure change. Elastance, the inverse of
compliance, is relatively intuitive since as stiffness decreases so does elastance and therefore PWV.
19
There was one relevant study in the literature. PTT changes above and below the segmental level of an
epidural block a regional block had been compared. 39
The investigators were interested in vascular wall
tone differences due to a sympathetic block that was confined to the lower trunk and legs. PTT in the arm
was used as a control. In a discussion more generally about vascular stiffness they noted that the function of
smaller peripheral resistance arteries were affected by the structural wall changes; in particular the ratios of
collagen, elastin and smooth muscle were important. They had not considered obstetric anaesthesia but the
relevance and potential application in the study of pregnancy and pre-eclampsia were clear.
In 2000, fortuitously, an analogue computer from Leiden University capable of transferring
electrocardiogram (ECG) data and photoplethysmography signals from routine monitoring equipment was on
loan to a colleague working with non-obstetric patients. The time interval between the peak of the ECG ‘R’
wave and the maximum rate of the plethysmograph upswing could be measured using this equipment. The
beat-to-beat PTT could then be computed, displayed and recorded in real time together with heart rate and
systolic and diastolic blood pressure. Responding to a request for ideas with the potential for pulse transit
time studies, I identified spinal anaesthesia in normal and pre-eclamptic subjects as a suitable ‘case’ for
study. We therefore established a collaborative project and successfully applied for a grant from the
Obstetric Anaesthetists Association. The grant subsequently funded additional equipment and a research
assistant for six months. There were three principal questions to answer:
1. Could PTT reliably track beat to beat changes during obstetric spinal anaesthesia?
2. What would the relationship be of PTT to be to mean arterial pressure (as measured non-invasively)?
3. Would PTT changes demonstrate the predicted differences in arterial stiffness in pre-eclampsia?
In order to maximise the chances of obtaining a grant, and after negotiating a collaborative approach with
both physiological and obstetric perspectives, we had opted to study PTT as a means of beat-to-beat
cardiovascular monitoring in spinal anaesthesia as the primary outcome. The study of pre-eclamptic subjects
was to be a secondary outcome but, apart from my own research interest, was also important for two reasons.
If arterial structural and functional changes caused increased arterial stiffness in pre-eclampsia, PTT changes
should reflect this. There should be a relative difference observed in both baseline PTT and also the rate of
20
change of PTT following spinal anaesthesia. If confirmed in a study it would support validation of the PTT
technique for the intended purposes. In addition it would corroborate the primary outcomes in our first two
studies on spinals in pre-eclampsia, and also in other related investigations as they were being reported in the
literature.
Methods
We had taken two years each to complete the previous two studies but, for this more demanding study that
would require a dedicated research assistant, there was only six months funding available. We therefore
recruited normal and pre-eclamptic subjects with varying degrees of proteinuria (therefore the subjects were
referred to as having ‘PIH’). The use of a dedicated research assistant to oversee physiological monitoring
improved the accuracy of cardiovascular data acquisition and recording. Although it was by necessity an
observational study, a critical element was the willingness of anaesthetic colleagues to delay the
administration of a vasopressor until clinically required. In other words, as part of their routine practice, they
did not always use a vasopressor prophylactically. This meant that PTT, heart rate and NIBP could be
recorded before, during and after the administration of the spinal anaesthetic up to a specified key time.
This time was called either the first intervention (of a vasopressor and/or a vagal blocking drug) or
alternatively the peak PTT recorded if there was no intervention. For the purpose of the study, the interval
between spinal administration and the peak PTT recording or anaesthetic intervention therefore represented
the maximum change in recorded cardiovascular response to the spinal. The inference, again for the purpose
of the study, was that this represented the maximum vasodilatation caused by sympathetic blockade. The
rate of change of PTT could then be measured and compared between the two groups.
21
Results
In an observational study of 73 patients 15 had severe pregnancy induced hypertension (as defined). In
answer to the questions posed when the study was designed:
1. Beat-to-beat PTT was consistently displayed and recorded using input from standard anaesthetic
monitors during spinal anaesthesia.
2. In the relationship between PTT and mean arterial pressure there was a significant correlation
(r2=0.55 P<0.0001) before and after anaesthesia
3. The interval representing the greatest change in PTT or the time to first intervention occurred 2.4
minutes after spinal anaesthesia in the normotensive group and 5.0 minutes in the hypertensive
group. Looking at the rate of change, PTT increased more rapidly in the normotensive group
compared to the hypertensive group by a factor of 4.
Discussion
Of the 73 patients investigated. 15 severely hypertensive patients were the maximum number of non
emergency subjects that could be recruited within the time frame of 6 months, even in a large 6,000 delivery
tertiary referral maternity unit. A condition of publication was that we calculate the sensitivity and specificity
of changes in PTT to indicate the onset of hypotension. From the ROC curves, for a decrease in mean arterial
pressure of, more than 10%, an increase in PTT of 20% was 74% sensitive and 70% specific. However there
were reservations on interpreting this particular statistical exercise, particularly if PTT is being considered as
a surrogate for arterial pressure. Arterial pressure itself causes increase in arterial stiffness; but arterial wall
tissues have visco-elastic properties and the relationship to PTT is non linear at high and low pressures
arterial pressures. Patient size, measurement artefacts and other variations in vessel wall characteristics can
influence the relationship between arterial pressure and PTT. As has been discussed, NIBP is not the gold
standard or benchmark of arterial pressure measurements. In theory there was therefore also an argument for
turning the editorial question the other way round. Could NIBP changes reliably track PTT changes? NIBP
22
measurements were at best available every two minutes. Conceivably there could be a delay of four minutes
before a blood pressure recording became available. Obstetric anaesthetists in routine practice therefore often
rely on symptoms such as dizziness, nausea and vomiting to indicate the acute onset of hypotension. Blood
pressure measurements: systolic, diastolic and the derived mean, only give a dimension of cardiovascular
function. Although there is a useful relationship between PTT and NIBP changes, PTT is clearly another
dimension of cardiovascular function. More research is needed to establish the role of beat to beat PTT as a
monitor of cardiovascular function in these circumstances. Whether this happens depends on developments
in the technology and physiology in other areas of continuous non invasive cardiovascular monitoring.
Publication and Impact of Research
The data was presented as conference abstracts separately for each part of the study i.e. first as a study of
arterial stiffness in the two groups, then as a study of the relationship between PTT and arterial pressure and
finally an assessment of PTT as a non invasive monitor of cardiovascular changes. The study had 22 Medline
citations by September 2010. The significance of the study specifically for the thesis was for the purpose of
understanding and studying the concept of changes in vascular properties during normal and preeclamptic
pregnancy. This was important for interpreting the outcomes of the first two studies and other related
publications in the literature. Together with a literature search, it therefore also formed an important
background for studying and understanding an important element of the pathophysiology. Thus there were
also implications for writing the editorial, the literature review and the thesis conclusion. The changes in
systolic, mean and diastolic arterial pressure trends supported the outcomes from studies 1 and 2. These
incidental findings were not specifically reported but are available in summary form (Table 1 of the
published article).
23
APPRAISAL 4
A reappraisal of the concept of hypotension following obstetric spinal anaesthesia
Linked publication page 72
Sharwood-Smith G, Drummond G B. Hypotension in obstetric spinal anaesthesia: a lesson from pre-
eclampsia. Br J Anaesth 2009; 102: 291-4.
Introduction to the Appraisal
This appraisal comprises three elements: a summary outline of the editorial, an expanded review to develop
the editorial themes and a conclusion to the completed thesis.
The Editorial
Introduction to the Editorial
The objective of the editorial was to reappraise the concepts ‘supine hypotensive syndrome’ and ‘inferior
vena caval compression’ in the light of the response of patients with severe preeclampsia to spinal
anaesthesia. The reappraisal forms part of a logical argument flowing directly from the outcomes of studies
1, 2 and 3 in this thesis. The desired outcome was, at minimum, to initiate a more general reappraisal and
influence the future direction of clinical practice, teaching and research.
Background
As a consequence of studies 1 and 2, together with the similar outcomes from other research, it has now
generally been accepted that spinal anaesthesia does not normally cause severe hypotension in severe
preeclampsia (subjects with severe hypertensive preeclampsia in the clinical circumstances of the studies
specified). Study 3 included an assessment of arterial stiffness that corroborated the findings of the other
studies using a novel approach. The main finding was that of a relatively delayed and quantitatively reduced
vasomotor relaxation following sympathetic blockade with a spinal anaesthetic. The structural and
functional cardiovascular changes of normal and preeclamptic pregnancy had been the subject of intensive
research over the previous twenty five years. These developments provided the pathophysiological basis for
24
understanding the observations made in studies 1, 2 and now 3. Critically, from a historical perspective,
these advances in understanding could have been predicted. Outcomes of Assali’s studies of some sixty years
ago did exactly this. Assali’s observations on hypotension following spinal anaesthesia in normal and
preeclamptic pregnancy contrasted with the subsequent obstetric anaesthetic consensus which favoured a
single cause caval vena compression theory of hypotension after spinal anaesthesia in normal pregnancy.
With hindsight, Assali’s research methods had some limitations, which are discussed in the review to follow.
However his work had important implications both at the time and currently. The historical significance of
these studies has been omitted from the teaching, research and clinical practice of obstetric anaesthesia.
It had originally been my intention to write an editorial to follow the three studies. My colleague, and co-
author of both study 3 and of the editorial, Dr Gordon Drummond whose main subspecialty interest for this
purpose is physiology rather than obstetric anaesthesia, had also independently perceived a problem in the
original vena cava compression theory. Rather than in the area of reproductive vascular biology, this was
more specifically in the initial interpretation of Guyton’s work: on the relationships between ‘cardiac output,
‘right atrial pressure’ and the concept of ‘venous return’. I was also interested in the significance of recent
concepts of venous capacitance. The advantage of a collaborative editorial was that ideas originating in
different subspecialist areas of anaesthesia, obstetrics and physiology, could be exchanged and combined; the
interpretation of clinical and scientific evidence as perceived by one author could be analysed and challenged
by the other. If there was any disadvantage to such a collaboration it was that the two perspectives and
priorities involved some final compromise; also that the review element of an editorial, the method chosen
for communication, was of necessity very concise. The second part of this appraisal, a review, is intended to
address this issue from my own perspective as the author of the thesis, in addition to its more general role as
a component of the thesis and a lead-in to the conclusion.
25
Summary of the editorial argument
Relatively severe hypotension occurs following spinal anaesthesia in normal pregnancy compared to non
pregnant and preeclamptic subjects.
This is assumed – the statement is based on outcomes of the preceding studies in the thesis and is also
extensively supported by other studies. It is also a premise of the relevant Cochrane Collaboration review.
These factors have been discussed in Appraisals 1-3.
The vena caval compression theory of hypotension in obstetric spinal anaesthesia is a concept with several
limitations
The history of this concept and its relationship to the ‘supine hypotensive syndrome’ is examined. The series
of case reports and studies which formed the basis for the vena cava compression theory are re-examined.
The method by the theory was modified to accommodate apparently contradictory evidence is examined. The
outcome of methods of prevention and treatment based on predictions from the theory are assessed.
The ‘pregnancy’ theory of severe hypotension after spinal anaesthesia in obstetric anaesthesia is revisited.
A series of studies by Assali are reassessed. Assali’s argument, on the basis of outcomes from the studies,
that the relative sensitivity to sympathetic blockade leading to severe hypotension was a characteristic
feature of normal pregnancy is reappraised.
Developments in cardiovascular physiology are important in reinterpreting earlier investigations
The implications of contemporary and later developments in cardiovascular physiology for two rival
theories are assessed. In particular the concepts of cardiac output and venous return in the context of the time
and also more recently are considered. Significant developments in the concept of venous capacitance and its
regulation are also discussed.
26
Developments in reproductive vascular biology support Assalis’s ‘pregnancy’ theory.
The significance for the two theories of hypotension following obstetric anaesthesia of international research
and development in this field are assessed. The ways in which these developments support Assali’s
‘pregnancy’ theory of hypotension are discussed.
Editorial conclusion: the single cause theory of hypotension following spinal anaesthesia, inferior vena
cava compression due to the supine hypotensive syndrome, is not supported.
Editorial Outcome.
A final answer on whether the intended outcome of the editorial has been achieved can only be assessed after
a period of several years. The initial aim has been achieved; this was to publish the editorial in a major
international journal of anaesthesia with a high impact factor. Medical academic and professional institutions
tend to operate their teaching and research programs within the boundaries of a conceptual framework, an
almost self evident fact that applies to science in general. The institutional pressures that can, and often do,
constrain the development of such a core conceptual framework have been studied extensively. 40
Change
and development ideally result from the accumulation of contradictory evidence. This is not usually a
revolutionary process but more often occurs as a result of a process of amendment. Alternatively core
frameworks can become completely redundant when the evidence in support of new conceptual structures
becomes overwhelming. This change or development is clearly fundamental to progress in science.
Academic discourse and the exchange of new ideas are basic requirements for this process to take place. The
arguments developed in the editorial and also in the thesis more generally are intended to contribute to the
discourse required for a change in the relevant concepts with important implications for teaching and
research.
27
Hypotension after obstetric spinal anaesthesia: a review of physiological concepts, their history and
development and the impact of advances in vascular biology
Methods
The literature search was essentially the same as that applied to the thesis as a whole. During the full period
of research, twenty years if the initial audit is included, there have been considerable developments in
information technology. These have been utilised as they have become available. Medical information and
research databases continue to accumulate publications from earlier decades. Initially it was necessary to
hand search journals and cross reference citations in reviews, research reports, studies and textbook chapters,
particularly when searching original articles published before 1960. Most recent searches have used
Medline, EMBASE, individual journal online databases and evidence based medicine resources such as the
Cochrane Reviews.
Hindsight and the quality of research
It is important to appreciate that in the pioneering era of obstetric anaesthesia, fifty to seventy years ago,
clinical practice and teaching were dominated by personal experience and opinion, often strongly expressed;
as for evidence, many studies were individual case reports or small series with data gathered retrospectively.
If prospective studies were performed the potential for selection bias was frequently characterised by a lack
of randomisation and control groups. The more recently established discipline, ‘Evidence Based Medicine’
(EBM) was a distant prospect. However the underlying philosophy of EBM predates the acronym and is not
confined to systematic reviews or randomised trials. 41
It would therefore be wrong to underestimate the
extraordinary efforts of the early physicians working in conditions very different from those of today. Some
collaborative studies were in fact carefully designed and used relatively sophisticated technology and
interpretation methods. The struggles and successes of these early pioneers to establish safer practice using
specialist skills and knowledge in a context of limited resources and rivalry between specialist disciplines
28
should not be underestimated. To be able to analyse and reassess this early research with the benefit of
hindsight is a particular luxury.
Inferior Vena Cava Compression and Spinal shock
In the 1950’s there was a very high anaesthetic mortality associated with spinal anaesthesia for
Caesarean section. Termed ‘spinal shock’, and characterised by a severe hypotensive reaction, there
was a direct mortality rate of 1%. Holmes, an Edinburgh anaesthetist, reported on this medical disaster in
1957. 42
He was aware that, during pregnancy, the recumbent supine position sometimes appeared to cause
compression of the inferior vena cava by the gravid uterus. In his view this phenomenon, part of the so
called ‘supine hypotensive syndrome’, was causally linked to ‘spinal shock’. 43
The first description of
supine hypotension in pregnancy has been attributed to Gideon Ahltorp; the case was reported in 1932. 44
He
later found that 30% of 650 women avoided the supine position and 6% found it impossible due to severe
symptoms. 45
Ahltorp suggested three possible causes, favouring the first: inferior vena cava occlusion, a
utero-cardiac reflex or pathological elevation of the diaphragm. It was noted that both aorta and inferior vena
cava could be compressed in the pathophysiology of this syndrome. Many reports and studies of supine
hypotension in pregnancy were subsequently reported. These reports were analysed in detail and reviewed by
Kinsella and Lohmann (1994). 46
Severe hypotension was reported in 2.5% to 20% of these patients. In
some patients, hypotension only occurred after twenty minutes in the supine position and it was even
reported following delivery. The words used to describe the phenomenon reflected uncertainly of the
aetiology. Ahltorp in 1932 referred to ‘cardiac insufficiency in the dorsal position in pregnancy, 45
while
other terms applied in the 1940-50 period included ‘fainting in pregnancy’ or ‘a vaso-vagal fainting reaction’
and ‘postural shock in pregnancy’. The final and perhaps appropriate title for this heterogeneous spectrum of
signs, symptoms and potential causes, ‘supine hypotensive syndrome’, was coined by Howard et al in 1953.
47 The heterogeneity of this syndrome is of particular importance in reassessing its relationship to severe
hypotension following spinal anaesthesia.
In his 1957 report on the cause and prevention of ‘spinal shock’, Holmes gave brief details of eleven
publications in the literature. 42
It is not clear as to the total number of individual case histories described
29
within these publications, one of which is stated to refer to seventeen individual patients. In his conclusion
he stated that, in his opinion, the cause of death was related to occlusion of the inferior vena cava and a
reduction of peripheral vascular resistance. He dismissed several unspecified alternative theories. He also
quoted in his article from Sir Robert Macintosh, a pioneer in the audit of anaesthetic deaths, ‘..... that
pregnancy itself could not predispose to hypotension after spinal anaesthesia, on common sense grounds’. In
retrospect and in the light of Assali’s work this might justifiably be considered a controversial view. It was
subsequently further endorsed in a standard textbook on spinal anaesthesia (Lee and Atkinson 1978). 48
Concluding his report Holmes made three basic recommendations to prevent death from ‘spinal shock’. He
recommended, in his personal opinion, that the susceptibility to hypotension be predicted from the patient’s
history. He also said that, to avoid hypotension, the height of block should be limited to segmental level T10.
If hypotension still occurred, he recommended turning the patient on her side and raising her legs. In the
1960 article referred to earlier, Holmes extended his concept by publishing two illustrative case reports of
hypotension after spinal anaesthesia. The choice of title is significant, ‘The supine hypotensive syndrome: its
importance to the anaesthetist’. 43
In the same year he contributed his own study of the supine hypotensive
syndrome in late pregnancy (not involving anaesthesia). 49
It was a clinical study of 500 patients and case
reports. In this study 2% of 500 patients experienced ‘severe’ hypotension associated with the supine
position. In Holmes’ opinion the low incidence of severe hypotension in this non anaesthetised series was
entirely compatible with the hypothesis that spinal shock was due to inferior vena caval compression The
explanation was as follows: the spinal anaesthetic removed the reflex vasoconstrictor tone in the legs and
then ‘revealed’ the vena caval compression.
The ‘pregnancy’ theory of hypotension after spinal anaesthesia
In the late 1940’s Assali, the Professor of Obstetrics and Gynecology at Cincinnati University and his
colleague Prystowsky were investigating cardiovascular changes in ‘toxaemia’ of pregnancy (severe
preeclampsia) with standardised selective (sensory and autonomic blockade) continuous spinal anaesthesia
using Procaine 0.2%. They demonstrated profound falls in blood pressure after spinal anaesthesia in normal
term pregnancy but negligible falls in preeclamptic and non pregnant controls using the supine position. 15
They had already obtained similar results with a systemic sympathetic blocking pharmacological agent. By
30
comparison with other studies of the time, these prospective controlled studies were elegant and well
designed. The weaknesses, by contemporary standards, were the limited number of subjects studied and the
fact that all pregnant subjects were supine and included both ante and post partum cases. However data was
carefully compared between each study group. It is also difficult to imagine an ethics committee approving
such a volunteer study some fifty or sixty years later, although this reservation also applies to research
published by many of the relevant investigators of the time. The most significant feature, in the light of later
developments in reproductive vascular biology, was the remarkable foresight of Assali who proposed a
humoral mechanism for the maintenance of blood pressure after spinal anaesthesia in preeclampsia and
further suggested that increased sympathetic tone supported the blood pressure in normal pregnancy.
Assali’s studies appear never to have been cited in the reports by Holmes or other investigators of inferior
vena cava compression and its relationship to spinal anaesthesia. They have only rarely been cited in the
anaesthetic literature since then, and in particular I have found no citation in any reviews or articles on the
history spinal anaesthesia in pregnancy. However a chance discovery during a recent literature search did
reveal convincing evidence of an academic dispute between protagonists of the two theories. It took the form
of a practice review (1958) of spinal anaesthesia in pregnancy by Williams, a UK obstetrician-anaesthetist. 50
Publication was followed by a vigorous dispute and an exchange of correspondence with Holmes. 51
Investigation of the Inferior Vena Caval Compression Theory
There were three approaches: the measurement of pressure in the lower inferior vena cava and femoral veins,
the radiological demonstration of compression of the inferior vena cava together with the linked collateral
vena azygos circulation, the demonstration of reduced cardiac output in the supine position.
The measurement of pressure in the ‘lower’ inferior vena cava was studied by Scott (1968) in subjects under
general anaesthesia while awaiting caesarean section. 52
It demonstrated increased pressure in the femoral
veins at the bifurcation of the inferior vena cava in the supine position. In the lateral position venous pressure
was less, but still not as low as non-pregnant levels. Pressure swings with respiration were transmitted to the
femoral veins relatively less that in non-pregnant subjects.
31
Kerr, Scott and Samuel (1964) used angiography to demonstrate complete supine occlusion of the inferior
vena cava with distension of the collateral vena azygos circulation in twelve patients having Caesarean
section under general anaesthesia for various indications. 53
Partial caval occlusion was also demonstrated
in the lateral position.
Lees, Scott, Kerr and Taylor (1966) studied cardiac output in eight conscious patients using a dye dilution
technique. 54
Mean cardiac output was twelve per cent less in the supine compared to the lateral position.
However in three subjects within the group the mean reduction was only six per cent. An associated feature
in these subjects was said to be the engagement of the foetal head. The interpretation was that relief of vena
caval compression was a consequence of that particular foetal position. In two subjects there were profound
reductions in arterial pressure and cardiac output (>50%) with bradycardia, suggesting a reflex response.
Interpretation of the results by the investigators was cautious, pointing out that the mechanism of
haemodynamic changes from the supine position in late pregnancy is varied and differs from patient to
patient i.e. no that pattern or single mechanism could be implicated. Scott additionally noted that in contrast
to the consequence of vena caval pressure at the pelvic outlet, a profound reduction in cardiac output
occurred when the obstruction was placed at the level of the hepatic vein. Significantly, with this
observation, he recognised the potential importance of the splanchnic circulation. He also suggested, based
on his observations, that a vasopressor could not restore cardiac output and therefore should not be given. In
later studies the cardiac output changes were less; for example Newman (1983) studied thirty subjects and a
control group using transcutaneous Doppler. 55
The maximum six per cent change in cardiac output
occurred on moving from supine to a left fifteen degree tilt, and there was no difference when the foetal head
was engaged.
Finally, and significantly, none of the investigations were performed during spinal anaesthesia.
The inferior vena cava compression theory is refined: preventive therapy is predicted and applied
The key features of the inferior vena cava compression theory were developed from Holmes’ work. His
interpretation was that the supine hypotensive syndrome and inferior vena cava compression represented a
32
single entitiy. 42, 43
As discussed, engagement of the foetal head was thought to relieve venous compression.
This was based on data from three patients in the Lees’ 1966 cardiac output study. For the purpose of the
theory, this observation effectively pinpointed the site of maximum physiological effect at or just above the
bifurcation of the inferior vena cava. In another illustrative case history Marx (1969) developed key features
of the theory, including the trapping of venous blood in the legs. 56
Based the concept as elaborated, Marx
developed the preventive techniques of lateral tilt and ‘acute hydration’ in which 1-2 Litres of crystalloid or
colloid were administered before the spinal anaesthetic. 57
The dramatic results of the early acute hydration
studies were never repeated; however the basic technique remained apparently unquestioned and was still a
standard practice some thirty years later. 58
Finally, in an editorial, Rout and Rocke (1999) addressed the
results of many studies which indicated the effective failure of the technique and, by implication, the basic
concept as originally proposed. 59
They also addressed the methodological problems of the early studies.
Spinal anaesthesia in obstetric clinical practice 1960 – 1990
The situation of spinal anaesthesia in obstetrics in the 1960’s, particularly for Caesarean section, was
reflected in the approach taken by Selwyn Crawford, one of the leading UK obstetric anaesthetists, in a
standard textbook. 60
He reported an 82% incidence of hypotension. He also indicated a lack of personal
experience with the technique by citing ‘authorities such as Marx’ who had advised the use of an intravenous
crystalloid preload and large (20 mg) boluses of ephedrine. He recommended, in line with Holmes’ earlier
advice, limiting the height of block to T10. Nausea and pain therefore caused a significant morbidity and
he recommended ‘a large dose of tranquilliser’; for example the administration of intravenous Diazepam
10 mg and Pethidine 50 mg at the beginning and end of the procedure. As to the cause of hypotension he
commented that there had been little attempt to discriminate between the respective contributions of
sympathetic block and caval compression. Interestingly, in their reluctance to use spinal anaesthesia for
Caesarean section, neither Selwyn Crawford nor Moir, author of another contemporary textbook, 61
mentioned the risk of litigation following contamination of equipment as specific contraindications to
spinals, or the incidence of post dural puncture headache.
33
In view of these reservations, spinal anaesthesia was very rarely administered in the UK in the subsequent
two decades. A three year survey of practice published in 1982 indicated only 3% of elective and 1% of
emergency Caesarean sections were performed under spinal anaesthesia. 61
Ten years later, increasing
experience in the USA with improved haemodynamic control using vasopressor drugs, and possibly better
quality spinal needles, had begun to reverse the situation. By 1992 in the UK, 52% of elective and 16 %
emergency Caesarean sections were performed under spinal anaesthesia (epidurals 19% and 30%
respectively). 62
Attempts to improve the therapies originally predicted to be effective by the theory
It is useful to consider the extensive resources that were applied over several decades in attempts to improve
and refine the limited efficacy of the predicted therapies. Particularly this applied to ‘acute hydration’ but
also to lateral positioning and various forms of leg compression. In a recent Cochrane Collaboration
Review, a total of 75 studies performed between 1992 and 1995 were selected for analysis according to the
stated evidence based criteria. 23 studies were of intravenous fluid therapy, 31 of drugs (largely vasopressor)
and 21 of physical methods (tilt and leg compression). 18
Many other (unselected) studies were also
published during this time and even more over the two previous decades. Additionally for each single
published study there are normally several investigations presented at international conferences. Although
relief of aortic and vena caval compression is suggested to benefit from lateral positioning, no method or
combinations of preventive strategies have been found to reduce the need to treat hypotension with a
vasopressor drug. By contrast with the recommendation of early investigators, safe contemporary anaesthetic
practice is based on the administration of one or more vasopressor drugs, often by continuous intravenous
infusion during the procedure. 63
An important additional theoretical prediction has also been challenged.
It had been taught for many years that multiple compared to singleton pregnancy leads to increased vena
caval compression and hypotension, particularly following a spinal anaesthetic. This has been confounded by
a recent large controlled study. 64
Even without this recent study it might seem surprising that the
fundamental basis of the concept was not reviewed at an earlier stage.
34
Haemodynamic changes in pregnancy: implications for the interpretation of theories of hypotension
after spinal anaesthesia
The vigorous debate between Holmes and Williams in 1958 indicated that the rival theories of ‘spinal shock’
were originally seen as mutually exclusive. Holmes’ theory, as developed by Marx, became dominant;
however Assali’s theory, which was based on earlier studies, is now supported by important later
developments in vascular biology.
A basic understanding of the physiological changes of pregnancy had preceded Assali’s work. Burwell et al
(1938) in animal and human work studied the increased cardiac output and oxygen consumption. 65
They
also developed a concept of the placental intervillous space as an arteriovenous anastamosis. More recently,
outcomes from primate and human studies (1987, 1988) provided confirmation of the decrease in vascular
resistance of normal early pregnancy. 25, 26
Other studies indicated that from the tenth week of gestation in
normal pregnancy there is a decrease in endogenous pressor responsiveness (especially to angiotensin II) due
to an endothelium dependant alteration of vascular smooth muscle, an increased synthesis of vasodilator
prostaglandins and an increased rate of nitric oxide synthesis leading to an increase in vasodilator tone. 27
In
response, according to the Guyton model, the renin-angiotensin system increased extracellular fluid and
hence blood volume. Consequent to these structural and functional vascular changes there is an increased
dependence on sympathetic vasoconstriction for the control of vascular tone. 29
Thus the use of
vasopressors to sustain arterial pressure and also, possibly, to control venous capacitance have become the
most important strategy for safe spinal anaesthesia in contemporary practice.
By contrast, in pre-eclampsia the vascular endothelium is damaged, probably in a mechanism involving
placenta derived proteins Flt2 and soluble endoglin which inhibit the functions of two angiogenic growth
factors, vascular endothelial growth factor VRGF and transforming growth factor beta. 66
The normal
vascular changes of pregnancy are thus reduced or absent; vasodilatation after spinal anaesthesia is thus also
reduced or prevented. 67, 68, 69
There is therefore less or no need for vasopressor support.
35
Venous Capacitance
While the focus has been on changes in the more easily studied peripheral arterial resistance, the contribution
of venous function, particularly venous capacitance and its regulation in responses to spinal anaesthesia may
ultimately prove to be very significant. Mobilisation of blood volume by vasoconstriction is largely a
function of the splanchnic veins. In the non pregnant state the splanchnic circulation contains twenty per
cent of the blood volume and receives twenty five per cent of the cardiac output. There is evidence to support
a similar situation in pregnancy. 70
The importance of this concept relates to the regulation of what has been
termed ‘venous return’ and hence cardiac output and arterial pressure. Gelman (2008) reviewed a
hydrodynamic model developed to illustrate the relationships between venous capacity and compliance. 71
The concepts of mean circulatory filling pressure, stressed and unstressed volumes are used to predict the
response of regulatory mechanisms under different conditions. Of most significance is the fact that
splanchnic and cutaneous capacitance veins are under a high degree of sympathetically controlled regulation
and are thus relatively densely supplied with adrenergic receptors. The potential consequences of
sympathetic blockade following spinal anaesthesia are clear. Lending support to the significant contribution
of the splanchnic circulation to venous capacitance, Jones et al explored the pro-vasodilatory state of
mesenteric veins in normal pregnancy. 72
Clearly, increased venous capacitance in normal pregnancy is
relevant to the failure of efforts to prevent spinal induced hypotension by administering large intravenous
volumes of crystalloid or colloid. Conversely, there is evidence to support parallel (to arterial) pathological
changes in venous function due to preeclampsia. 73
In this situation the normal pregnancy driven increase in
blood volume does not take place. However there is still a lack of studies on this aspect of venous function
during pregnancy.
The cardiovascular system: dealing with complexity
The heterogeneity of response to the supine position in late pregnancy was noted by the early investigators.
Despite these observations it may have been the apparent and misleading functional simplicity of the human
cardiovascular system that influenced development of the inferior vena cava compression theory in the
1960’s. A four chamber heart comprising two pumps in series but cycling synchronously is relatively easy
to understand. However the fact that the pulmonary and systemic circulations operate as different, low and
36
high, pressure systems together with the need to maintain a functional cardiopulmonary circulation under
many different conditions begins to introduce complexity. The role of the Frank-Starling mechanism in
balancing the pulmonary and systemic circulations was well established by the 1930’s. So too was the
relationship between arterial pressure, flow and peripheral resistance and its analogy to Ohm’s law. This
physiological concept was coincidentally under development by Guyton and others (1959) at the same time
as Holmes began his investigation into spinal shock. 74
Of interest is the fact that another of the early
investigators (Scott 1964) considered that vasopressors should not be given to manage the supine
hypotensive syndrome when associated with anaesthesia. 53
The reasoning was that since the cause of
hypotension was due to blood being trapped in the legs, cardiac output could not be increased by using this
therapy. Investigators, including Scott, had commented on the possible importance of the splanchnic
circulation; but the option of developing this idea was limited by the, then current, concept of cardiac output
and its relationship with venous and arterial function.
It is helpful, in analysing the development of the two theories of spinal induced hypotension, to examine the
more general way this complexity has been dealt with. Standard cardiovascular physiology textbooks outline
these basic principles and describe the haemodynamic system as a complex system with multiple layers and
feedback loops. 75
Fast extrinsic regulation, for example by the sympathetic system is complemented by
slower intrinsic autoregulatory vascular reflexes dependant, among other factors, on local metabolic
conditions and the basic myogenic response. Structural and functional haemodynamic changes are then
superimposed on this underlying system during pregnancy. The consequences of administering a spinal or
epidural are therefore not simply restricted to the immediate direct effects of the central neural, including
sympathetic, blockade. There are clear implications for understanding the more complex evolving
haemodynamic responses to regional anaesthesia in many key clinical situations in the labour ward and
operating theatre.
37
Further complexity is added by the heterogeneity of human physiological responses. This heterogeneity was
particularly noted in the 1960’s by some investigators of the supine hypotensive syndrome in its relationship
to ‘spinal shock’. 54
A useful illustration of the way this affects cardiopulmonary responses has been studied
in a hypoxic environment. 76
It is, in part, associated with the evolution of organ systems and the 5%,
between individuals, variation of the human genome. For example although the protein encoding genes are
shared in common, there are copy number variations and differences in gene expression. There are also
differences in numbers of polymorphisms in the protein coding control and transcription elements. Other
more obvious possible causes of heterogeneity are related to anatomical differences and the presence of
incidental pathology. The observation that up to 20% of normal parturients do not experience profound
hypotension is very relevant for future research in obstetric spinal anaesthesia is. A possible normal variation
in pregnancy induced vascular changes, the presence of occult preeclampsia and anatomical differences are
potential hypotheses to explore.
Physiologists have introduced a variety of models to accommodate complexity and predict responses.
Electronic circuitry, hydrodynamics, mathematics and computer systems are the most familiar models. The
theoretical basis for this kind of modelling can prove baffling to the clinician. However the advantage is that
relatively simple predictions can be derived from the models and applied therapeutically in clinical practice.
The cardiac function curve (Guyton 1973) which describes the relationship between cardiac output, venous
return and right atrial pressure is probably the most familiar for anaesthetists working in the operating
theatre, maternity or intensive care unit. 74
The important issue is that the abstract nature of the models and
the apparent simplicity of the clinically applied predictions can obscure the limitations of the model. Over
time, such a model, often after being taught to trainees didactically and reproduced in textbooks, can become
perceived as a permanent reality. However in the field of applied physiology these models are not set in
stone but are constantly subject to reappraisal, modification and occasionally abandonment as physiological
research and clinical observation generate contradictory or confirmatory evidence. An example illustrated
by Malpas, Montani and Osborn (2009) is that of the Guyton computer based model which has been updated
to deal with the relationships between blood volume regulation, arterial pressure and the renin-angiotensin
38
system. 78
Changes in blood volume-arterial pressure relationships and possible insights into acute versus
long term responses in pregnancy are of interest; for example in the interpretation of the failed ‘acute
hydration’ prophylactic therapy. Updating the model is a therefore dynamic, not a static process. This
illustrates a particular problem for clinical specialisation. In this situation, for example, subspecialties can
operate in relative isolation. Obstetric anaesthesia was institutionalised in the UK and USA in the 1970’s.
The first president of the Obstetric Anaesthetists Association understandably made it clear that the emphasis
had been on safety, rather than science, in what is largely practical subspecialty. 3 This remains the situation
some forty years later. Recent textbooks of anaesthesia reflect the failure to update the concept of inferior
vena cava compression in obstetric spinal anaesthesia. 17
39
CONCLUSION
An audit of clinical practice followed by two prospective studies challenged the prevailing concept that
spinal anaesthesia, by comparison with general or epidural anaesthesia, causes potentially dangerous
hypotension in severe preeclampsia. The first study compared spinal versus epidural anaesthesia and
suggested that both techniques were relatively safe in terms of hypotension. The second tested the hypothesis
that the presence of preeclampsia in otherwise stable patients was associated with resistance to severe
hypotension. These investigations compared the requirement for vasopressor drugs to sustain arterial
pressure within predetermined limits. A third study used a different approach; pulse transit time
measurement offered a novel technique for studying beat to beat cardiovascular monitoring. It also
compared arterial stiffness between normal and preeclamptic subjects. Arterial stiffness differs between
normal, normal pregnant and preeclamptic subjects due to the different structural and functional vascular
properties characteristic of each group. Additional cardiovascular data from study 3 also corroborated the
study 1 and 2 outcomes.
Preeclampsia is known to reduce or prevent the development of cardiovascular changes in normal
pregnancy; this raised the possibility that the cardiovascular changes of normal pregnancy are an important
factor in the development of severe hypotension after spinal anaesthesia. Since the second study suggested
that the presence of severe preeclampsia was associated with resistance to hypotension it became important
to reassess the original underlying concept; this was based on the theory that inferior vena caval
compression, when associated with the spinal induced sympathetic blockade, was the single cause of severe
hypotension normally experienced following obstetric spinal anaesthesia. The third study gave additional
indirect support to Assali’s alternative hypothesis, that the structural and functional vascular changes of
normal pregnancy are a cause of hypotension following a spinal anaesthetic.
The final part of the thesis followed logically from the outcomes of studies 1, 2 and 3 and also from other
supporting studies. In this section the concepts ‘supine hypotensive syndrome’ and ‘inferior vena caval
compression’ and their role in explaining the aetiology of severe hypotension following spinal anaesthesia in
normal pregnancy were reappraised. A published editorial introduced the arguments for the reappraisal.
40
These arguments were extended, in the thesis, by a more comprehensive literature review. The series of case
reports and studies which formed the basis for the vena cava compression theory were appraised. Several
prophylactic measures based on physiological responses predicted by the vena cava compression theory were
also examined. An essential part of the original theory had been the precise location of effective inferior
vena caval compression at the pelvic brim. In the theory, trapping of venous blood in the legs was said be
aggravated by administration of a spinal anaesthetic; the mechanism was its action in blocking the normal
autonomic vasopressor reflex. There were several limitations to the concept. The supine hypotensive
syndrome was known at the time to have more than one possible cause i.e. not only vena cava compression.
Early cardiac output studies showed a 12% reduction in the supine position and angiography did demonstrate
supine compression of the inferior vena cava and aorta. However later investigations showed a smaller
reduction and failed to confirm the hypothesis that the engaged foetal head relieved the compression. The
latter being the basis for fixing the site of vena caval compression. The studies did not differentiate between
the relative effects of aortic and vena cava compression. There were other reservations: none of the
investigations were undertaken during spinal or even epidural anaesthesia and no study demonstrated
trapping of venous blood in the legs. Early investigators did acknowledge that the function of the splanchnic
circulation might be important after spinal anaesthesia but the idea was not developed further. More recently
there have been significant developments in the concept of venous capacitance and its regulation, which is
under autonomic control. Therapeutic measures were based on predictions derived from the theory of
venous trapping and included the prophylactic administration of 1-2 L of intravenous crystalloid or colloid,
the use of lateral positioning and various methods of leg compression. Lateral positioning or tilt was a logical
manoeuvre in view of the aortic and vena caval compression that had been demonstrated. However none of
the methods individually or in combination have been shown to reliably prevent the need to treat
hypotension with vasopressor drugs.
An alternative theory based on earlier studies by Assali was reassessed. Assali’s argument, on the basis of
outcomes from his studies, was that the relative sensitivity to sympathetic blockade leading to severe
hypotension was a characteristic feature of normal pregnancy. This theory is supported by outcomes of
41
studies 1,2 and 3 in the thesis and also by other published investigations. It is also supported on theoretical
grounds by more recent developments in reproductive vascular biology.
The original theory underestimated the heterogeneity of cardiovascular responses to supine and other
positions in late pregnancy. Several later developments have contributed to the need for a reassessment: the
relative complexity of cardiovascular physiology, the potential significance of venous capacitance and its
regulation and the impact of pregnancy induced vascular changes. Physiological models designed to
accommodate this complexity and make therapeutic predictions are normally modified or abandoned over
time, as investigations confirm or refute previous observations or assumptions. The basic concepts
underlying hypotension in obstetric spinal anaesthesia must similarly be updated. For this purpose it is
important to engage in the relevant multidisciplinary exchange of ideas and research outcomes. In this way
obstetric anaesthetic teaching, clinical practice and research can be better directed. The pioneer obstetric
anaesthetists who developed the original ideas and investigations would have expected no less.
42
RESEARCH CONTRIBUTIONS
I developed the original ideas for the first two studies when reviewing anaesthetic practice in our unit. The
study designs resulted from collaborations with Dr Vicki Clark who co-ordinated data collection procedures.
Dr Clark and I performed most of the clinical studies. In the first study we were assisted by Dr Elaine
Watson who also presented data in abstract at the Obstetric Anaesthetists Association (OAA) Annual
Conference in 1998. In the second study we were assisted by Dr Alexandra Stewart. Dr Clark presented the
conference abstract at the OAA in 2001. I performed the statistical analysis on the second study with
assistance from Dr Bernhard Heidemann. I drafted and coordinated the editing of both manuscripts for peer
review and final publication.
I developed the initial idea for the third (PTT) study as an obstetric application of a technique already in use
by Dr Gordon Drummond. The subsequent design was a collaboration with Dr Drummond. Our research
assistant, Jean Bruce, coordinated studies and made the initial analysis of cardiovascular and other patient
data. I performed a number of the patient studies when Jean Bruce was unavailable. Jean Bruce and I
presented the data in abstract at the OAA and the International Society for the Study of Hypertension in
Pregnancy (2002). I made the initial draft for publication after which it was jointly edited with Dr
Drummond who performed the statistical analysis and coordinated responses to peer reviewers and journal
editor.
The editorial was an idea that I began to develop after the second study. Dr Drummond had also
independently developed some ideas on related aspects of cardiovascular physiology. The final result was a
collaboration in which ideas were exchanged and discussed extensively before finalising a draft for
publication.
The original ideas for a unitary theme for the thesis, the appraisals, the literature review and the conclusion
are otherwise entirely my own contribution.
43
ACKNOWLEDGEMENTS
These studies could not have been completed and published without the enthusiastic support and
collaboration of Dr Vicki Clark and Dr Gordon Drummond. Jean Bruce, who incidentally won the free paper
prize when she presented the PTT study at the OAA meeting in Nottingham, was engaged in the project on a
full time basis for six months. My consultant obstetric anaesthetic colleagues patiently supported the studies
as did our obstetric medical colleagues and the midwifery and operating theatre staff in the Simpson
Maternity Unit. Dr Anne McCrae and Dr Bernhard Heidemann contributed more informally as ideas
developed over many years. Finally, the projects could not have been completed without the interest and
support of our patients. Professor A Dahan, University of Leiden, loaned the analogue computer for
processing ECG and optical plethysmograph signals in the PTT study. The third study was also supported by
a grant from the OAA.
44
COMPETING INTERESTS
There was a grant from the OAA to support the PTT investigation. Jean Bruce and I received discretionary
grants from NHS Lothian to travel to the 2002 International Society for the Study of Hypertension in
Pregnancy Conference in Toronto where we both gave presentations (two oral and one poster). Travel and
subsistence grants were awarded by NHS Lothian and the Department of Anaesthetics for abstract
presentations of all the other studies at OAA conferences. There are no competing commercial interests.
45
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Audit of delivery unit management of severe preeclampsia (SPE) finds that experienced anaesthetists are administering spinal
anaesthesia (SA) for Caesarean Section against a 40 year old consensus and clinical guideline
Study 1Test the hypothesis that SA is relatively haemodynamically safe compared to
epidural in SPE
Study outcome suggests that SA with its rapid onset of sympathetic block is relatively safe. Study data also raises two questions.1. Does SPE confer resistance to the hypotension seen after SA in normal pregnancy? 2. If so, does this challenge the fundamental theory of caval compression as the single cause of severe hypotension following SA in
normal pregnancy? (the vascular changes of normal pregnancy that are suppressed in SPE may be an important cause of hypotension)
Study 2Test the hypothesis that SPE
confers resistance to the hypotension experienced after SA in normal
pregnancy
Study 2 suggests patients with SPE are resistant to severe hypotension after SA. Study 3 (PTT) in one outcome corroborates this.Outcomes from other centres confirm. The longstanding consensus that the severe hypotension in normal pregnancy seen following SA due to a single cause – compression of the inferior vena cava (IVC) by the gravid uterus – is also thus challenged.
Journal editorials indicate persisting reservations on the outcomes of studies 1 , 2 and similar studies from other centres
Study 3Test the hypothesis of increased
arterial stiffness and delayed relaxation in SPEusing study pulse transit time (PTT)
changes
Editorial Published
Objective(Extended by a literature review in the thesis)
To update the concept of hypotension after obstetric SA.
To review the implications of studies 1, 2 and 3 and relevant studies from other centres.
To review the history and evolution of the single cause IVC compression theory, its basis in cardiovascular
physiology and its predictions on prophylactic therapy to manage the hypotension.
To recover and review Assali’s alternative (vascular changes in pregnancy) theory
THESIS ALGORITHM
CONCLUSION
Inrernatmnnl Journalof Ohsretric Anesthesia (1999) 8, 85 89 Q 1999 Harcourt Brace&Co. Ltd
ORIGINAL ARTICLE
Regional anaesthesia for caesarean section in severe preeclampsia: spinal anaesthesia is the preferred choice
G. Sharwood-Smith, V. Clark, E. Watson
Department of Anaesthetics, Simpson Memorial Maternity Hospital, Edinburgh
SUMMARY Standard textbooks advocate epidural rather than spinal anaesthesia for caesarean section in severe preeclampsia. The basis for this recommendation is the theoretical risk of severe hypotension but no published scientific studies have been identified to support this assertion. We therefore designed a prospective
study to compare spinal versus epidural anaesthesia in severely pre-eclamptic patients requiring hypotensive therapy. Following ethics committee approval, 28 women with preeclampsia requiring hypotensive medication who were scheduled for urgent (not emergency) or elective caesarean section consented to receive epidural or spinal anaesthesia by random assignment. Seven patients were excluded due to protocol violations. Four of these
were in the epidural group of which two were excluded due to inadequate analgesia. No spinal patient was excluded because of inadequate analgesia. Mean ephedrine dosage was 5.2 mg (range O-24 mg) in the spinal group and 6.3 mg (range O-27 mg) in the epidural group. Six of the 11 patients in the spinal group required no ephedrine as did five of 10 in the epidural group. One patient in the spinal group suffered from mild intraoperative pain. By contrast in the epidural group three patients had mild pain and four others had pain severe enough to warrant intraoperative analgesia. There were no differences in neonatal outcomes. These findings support recent studies suggesting the safety and efficacy of spinal anaesthesia in this group of patients.
INTRODUCTION
Controversy has surrounded the choice of anaesthesia in severe preeclampsia.’ The concern has been that the placental circulation may be compromised by severe hypotension following regional techniques.2 Epidural anaesthesia is now generally accepted for these patients but spinal anaesthesia is sometimes consid-
ered to be contraindicated.3 In contrast to the prevail- ing view an internal audit in our own unit revealed an increasing tendency by anaesthetists to use spinal anaesthesia, finding improvement in both quality of block and onset time but without observing severe
hypotension. A retrospective study published in 1992
Manuscript accepted December 1998
Dr Geoffrey Sharwood-Smith, Consultant Anaesthetist Dr Vicki Clark, Consultant Anaesthetist, Dr Elaine Watson,
Senior Registrar, Department of Anaesthetics, Simpson Memorial
Maternity Hospital, Lauriston Place, Edinburgh EH3 9YW,
Scotland, UK.
Correspondence to: Dr G. H. Sharwood-Smith, Consultant Anaesthetist, Royal Infirmary, Edinburgh EH3 9YW, Scotland,
UK. Tel: 0131-536-4274/3651; Fax: 0131-536-3672;
E-mail: [email protected]
85
supported this change in practice.4 We therefore set out to compare haemodynamic stability and quality
of analgesia prospectively in spinal and epidural anal- gesia for severe hypertensive preeclampsia.
METHOD
We recruited 28 women with severe preeclampsia requiring anti-hypertensive therapy who were sched- uled for elective or urgent but not emergency delivery, i.e. non-labouring patients who were suitable for
either technique of regional anaesthesia. The diagno- sis of preeclampsia was made by obstetric medical staff following the onset of hypertension and protein- uria after 20 weeks gestation. Standard criteria5 are applied in our unit as follows: proteinuria is present as 2+ test strip albuminuria in a mid stream specimen of
urine, hypertension is defined as a diastolic pressure of more than 110 mm Hg on any one occasion or more than 90 mm Hg on two or more occasions at least 4 h apart. Patients were recruited on the basis of a sus- tained hypertension of more than 110 mm Hg denot-
ing severe preeclampsia. They were treated with labetalol f nifedipine as indicated according to our
Digital thesis publication by permission of Elsevier Ltd 2011
86 International Journal of Obstetric Anesthesia
unit protocol. The study exclusion criteria were as fol-
lows: eclampsia, anti-convulsant therapy, coagulopa- thy, patient refusal of regional blockade and patients who were outside 1.53-1.7 m in height or over 100 kg weight. Written, informed consent was obtained and
the patients were randomized to receive either spinal or epidural anaesthesia.
Ranitidine was given preoperatively either orally in a dose of 150 mg or 50 mg i.m. or iv. according to the degree of urgency of the delivery. sodium citrate
0.3 M 30 ml was administered orally in the anaes- thetic room. Baseline systolic blood pressure was measured 5 min after arrival in the anaesthetic room
and before instituting any invasive procedures. A blood pressure 30% below baseline systolic was set as the level for intention to treat.
The regional block was sited in the left lateral posi- tion at the second or third lumbar interspace. The patient was then turned supine with a wedge under the right buttock to avoid aorto-caval compression. Spinal anaesthesia was instituted with a 24 gauge
Sprotte needle and 2.75 ml of heavy 0.5% bupiva- Caine. Epidural anaesthesia was performed with a 16 guage Tuohy needle through which 3 cm of a lateral eyed catheter was placed in the epidural space. Four ml of 2% lignocaine was given as a test dose and if
negative after 5 min was followed by 16 ml of plain 0.5% bupivacaine. The blocks were tested at 5 min intervals and when analgesia to pinprick with a 27 gauge dental needle reached T5 bilaterally (T5 being
the first unblocked segment), surgery was allowed to proceed. In the epidural group, supplementary 0.5% bupivacaine, 1.5 ml per unblocked segment, was given until analgesia to T5 was achieved. After 11 patients had been randomised there was concern as to the rela-
tively poor quality of epidural block and fentanyl 75 pg was added to the epidural solutions.
Apart from 250 ml iv. Hartmann’s solution while instituting the block, we restricted perioperative fluids
to 80 ml/h plus losses. In keeping with experience reported by other units6 we base the management of these patients on a protocol comprising guidelines on fluid restriction and blood pressure control. Our inter- nal audit confirms a reduction in complications with this simplified regime.7
The patients were monitored with ECG, pulse oximetry and automated non-invasive blood pressure recordings at 2 min intervals. Oxygen was given at 4 Wmin via a Hudson mask until delivery when 10 units of synthetic oxytocin (Syntocinon) was
given i.v. If discomfort or pain was felt during surgery
Entonox and/or morphine was given as required. If these measures were not effective or if the initial block failed to reached the specified T5 height the patient
was withdrawn from the study and an alternative anaesthetic administered as appropriate.
Ephedrine in 6 mg increments was given at 2 min intervals if the patient exhibited symptoms associated
with hypotension (nausea, vomiting or dizziness) or if the systolic blood pressure fell below 30% of the base- line. Intraoperative blood loss was replaced with Hartmann’s solution or blood as judged clinically appropriate. The presence of nausea, vomiting or bradycardia was recorded.
Neonatal Apgar scores were recorded at 1 and 5 min by a paediatrician blinded to the anaesthetic tech- nique. Further neonatal outcome was obtained from the paediatic casenotes.
Postoperatively mothers were monitored in our high dependency unit for a minimum of 24 h where
intravenous PCA morphine was administered. Fluid administration followed the unit protocol. A ques- tionnaire was sent to the mothers approximately 1 month after delivery to determine their health status.
RESULTS
The mean age of the women was 29.7 years (range 23-39) in the spinal and 27.3 years (range 20-35) in
the epidural group. The mean gestational age of babies was 33.8 weeks (range 29939) in the spinal and 35.0 weeks (range 2641) in the epidural group.
Of the 28 women recruited, seven were excluded because of protocol violations. Of the three exclusions
in the spinal group none were excluded due to failure of analgesia. In one, the spinal was not performed as stipulated in the protocol, in another, more than 250 ml of Hartman’s solution was given pre-operatively and the third patient was found to be below the range stipulated for height. Of the four exclusions in the
epidural group two were for inadequate analgesia. One of these epidurals was converted to general anaesthesia and the other to spinal. The other two
epidural exclusions were unrelated to analgesia. One patient was found to be above the stipulated weight range and the other had a period of hypotension but was not given ephedrine according to the protocol. This left 21 women for analysis, 11 in the spinal and 10 in the epidural group.
Only one patient in the spinal group had discom- fort during surgery but no treatment was required. By contrast seven out of the 10 women who had epidu- rals complained of pain during surgery. Three epidu- ral patients required intraoperative morphine. This occurred despite earlier supplementary local anaes- thetic top-ups to achieve pinprick analgesia to T5 (Table 1). The poor quality of analgesia in the epidu- ral group, including the two exclusions converted to
Regional anaesthesia for caesarean section 87
Table 1. Epidural data
case age epidural adverse intraoperative ephedrine problems gestational age Apgar at
number (years) volume* events usage (mg) at one month (weeks) 115 min
2 20 4+16 nil 0 nil 31 719
3 31 4+16 pain (morphine) nausea + 12 nil 33 519
vomiting 6 30 4+16+7.5 pain (Entonox) 6 nil 26 519
8
12
17
33
24
22
4+ 16+6
4+16+4.5+F
4+16+F
nausea pain (morphine)
slight pain (no Rx)
slight pain (no treatment),
6 nil 32 s/9
0 DNRQ 34 919
12 DNRQ 35 919
19
20
23
35
4+16+6+F
4+16+F
nausea nil 0 renal hypertension 31
pain (Entonox + morphine) 0 nil 41
819
919
22 24 4+4+ 16+F
23 31 4+16+3+F
nausea + vomiting
repeat test dose
slight pain (no Rx)
21
0
nil
essential
hypertension
40 818
35 919
*2% lignocaine + 0.5% bupivacaine (ml)
F = Epidural fentanyl
DNRQ = Did not return questionnaire
Table 2. Spinal data
case age adverse intraoperative ephedrine problems gestational Apgar at
no (years) events usage (ms) at 1112 age (weeks) l/5 min
7 33 nil 3 DNRQ 36 919
9 23 nil 24 nil 33 919
11 33 nil 0 nil 34 919
14 33 bradycardia, light-headed 6 nil 35 s/9 16 28 pain (no treatment) nausea 0 BP still high 36 919 18 30 nil 12 DNRQ 36 919 21 23 nausea 0 nil 33 517
24 39 nil 0 nil 30 819
25 32 nil 0 nil 39 919
27 30 nausea 0 DNRQ 31 919
28 23 nil 12 DNRQ 29 819
DNRQ = Did not return questionnaire
spinal and general anaesthesia, posed an ethical dilemma. A pilot study had suggested that 80 patients would have been required for an 80% power to detect a significant difference of 6 mg ephedrine between the groups. However, this analysis became of secondary importance following our findings of relatively inef-
fective analgesia in the epidural group. The study was therefore referred for consultation with senior col- leagues and the ethics committee chairman; it was agreed that it would be appropriate to conclude any further randomisation to the epidural group after studying 28 patients and to report the results. The
data for these patients are presented in Tables 1 and 2. The ephedrine requirements of the two groups
were remarkably similar. The spinal group had a mean ephedrine requirement of 5.2 mg (range O-24 mg) and the epidural group 6.3 mg (range O-27 mg). No ephedrine was required for six out of the 11 women in the spinal group and five out of the 10 in the epidural
group. Neonatal Apgar scores were similar for the two groups. All babies survived at the 1 month follow-up.
In our unit the indications for invasive haemody- namic monitoring are major haemorrhage, pul- monary oedema and acute renal failure. No patients in the study required this form of monitoring.
Fifteen women returned the questionnaire sent 1 month postpartum. Of these, one woman in the spinal
group had persistently high blood pressure. Persistent hypertension also occurred in two women in the epidural group; a renal cause was found in one.
DISCUSSION
Preeclampsia affects 6-8% of all pregnancies. The precise cause remains to be elucidated but when severe there is vasoconstriction involving both resistance (arterial) and capacitance (venous) sides of the
88 International Journal of Obstetric Anesthesia
circulation with an associated hypovolaemia.8 There is widespread maternal vascular endothelial damage, increased sensitivity to endogenous vasopressors and a functional imbalance between prostacyclin and thromboxane A,. Nitric oxide is normally synthesised
in the intact vascular endothelium and is thought to play a fundamental role as a vasodilator in the circula- tory adaptation of normal pregnancy.9 Clinical expe- rience of the relative resistance to hypotension
following central neural blockade lends support to this peripheral circulatory mechanism. Additionally, it has also been observed that untreated pre-eclamptic patients are resistant to supine hypotension.“’
A literature search for scientific evidence to sup- port the recommendation that spinal anaesthesia be avoided in severe preeclampsia proved fruitless. The only explanation would appear to be anxiety that the
hypotension typical of non pre-eclamptic parturients would also occur in these patients thus reducing an already compromised placental circulation.“a’2 More recently, epidural anaesthesia has come to be accepted
as suitable for severe preeclampsia but the more pro- found and rapid sympathetic block induced by spinal anaesthesia in non-preeclamptic patients has meant a continuing rejection of this technique by some anaes-
thetists.‘j Three recent studies have cast doubt on the view that spinal anaesthesia leads to severe hypoten- sion in these patients.4,6,‘4 Following one of these stud- ies, a retrospective review of 48 caesarean sections in
severely preeclamptic patients, it was suggested that the dogma that spinal anaesthesia is contraindicated in the severely pre-eclamptic patient should be
reassessed.4 There have been, to our knowledge, no previous
prospective studies of the relative merits of spinal and epidural anaesthesia in this group of patients. The explanation is almost certainly due to the difficulties
inherent in such a study. Despite a generally accepted classification of this multi-system disorder’ there are still semantic difficulties. Hypertension without pro- teinuria arising after 20 weeks gestation is referred to as pregnancy induced hypertension. Essential hyper- tension arising coincidentally may only be identified at the postpartum stage. It is also important to appre-
ciate that severe preeclampsia may present with a hep- atic or haematological disorder rather than hypertension.8 The investigation was specifically con- cerned with our most commonly presenting group: patients with classical signs of severe hypertensive preeclampsia who have been stabilized according to our unit protocol. Despite the number of tertiary referrals available to our large obstetric unit these problems meant that the study took 24 months to complete. The seven excluded patients reflect the diffi- culty of attempting to study comparable groups.
Poor analgesia in the epidural group prompted the decision to add epidural fentanyl 75 ltg after the eleventh randomization. This may seem inconsistent with what was otherwise a rigorously applied protocol; however four out of the six patients to whom epidural
fentanyl was administered experienced pain of some degree suggesting that this alteration to the protocol made little material difference to the outcome. There are several possible explanations for the inadequate analgesia provided in the epidural group. It is possible
that pathological changes in preeclampsia such as oedema may affect the uptake of anaesthetic agent within the epidural space. We also considered the possi- bility that an alternative epidural technique might have improved the efficacy of blocks. Nevertheless, 0.5% bupivacaine with 75 ltg of fentanyl in the appropriate
volume is considered a standard and effective method in the UK and elsewhere. Lignocaine 2% with the addi- tion of epinephrine 1:200 000 was a possible equivalent choice; however, we do not add epinephrine to regional analgesia in preeclampsia because of the risk of inad-
vertent intravenous injection. Warming the solution” and adding bicarbonate have been shown to speed the onset of the block but not to improve efficacy. I6
Another consideration is our method of sensory testing. It has been argued that the segmental level at which touch rather than pinprick sensation is lost will
better predict the adequacy of a regional block. Since the spinal group demonstrated a uniformly high qual- ity of block and loss of pinprick sensation to at least T5 was required in both groups this should, in theory,
not be an issue. In practice, as Russell has suggested, a spinal often seems to provide a superior block com- pared with an epidural for a given level of anaesthe- sia.” Bourne et al. have pointed to what may actually
be the critical factor: epidural anaesthesia may leave unblocked segments within the main area blocked or in the most caudal dermatomes.‘* Increasing experi- ence of spinal anaesthesia for elective caesarean sec- tion in non preeclamptic parturients gives further support to a preference for this method. In a study comparing spinal (n=47) versus epidural (n=47)
anaesthesia, Riley et al. found that 38% of the epidu- ral group required supplementary analgesia compared to 17% of the spinal group. The time efficiency and quality of analgesia provided by spinal blockade appeared to set a gold standard which was superior to that provided by epidural anaesthesia.19 In view of the number of patients in our study we can not com- pletely exclude the possibility that the difference was due to chance. However, after 28 randomizations there was clearly an ethical issue and, in accordance with the uncertainty principle, we were no longer ‘sub- stantially uncertain’ as to which of the two techniques were suitable for the patients under study.”
Regional anaesthesia for caesarean section 89
A salutary discovery in our literature search was the study by Assali et al. in 1950.*’ They set out to resolve conflicting evidence as to the effect of sym- pathetic blockade in normal and ‘toxemic’ (severe hypertensive pre-eclamptic) pregnancy. Ethical con-
siderations would preclude undertaking such a study now and, although a statistical test was applied, the numbers were small. It was, however, an elegantly designed study which included a comparison of the effects of high spinal sensory blockade pre- and post-
partum on 10 normal pregnant women and 12 preg- nant toxemic women. There were five non-pregnant controls. Profound falls in blood pressure occurred in the normal pregnant women whereas the toxemic patients were only minimally affected. Apart from the fact that this study appears to have been forgotten, it
is also notable for the remarkable foresight of the authors who suggested that blood pressure in toxemic pregnancy was maintained by a humoral rather than neurogenic mechanism. Clinical support for these
findings was reported in a retrospective review of obstetric spinal anaesthesia 12 years later.**
Our study has added to a body of evidence which indicates that spinal and epidural anaesthesia do not cause profound hypotension in severe hypertensive preeclampsia. When vasopressor support was required for either technique the dose of ephedrine
was small compared to that reported in normal par- turients.23 Spinal anaesthesia is to be preferred in terms of quality of analgesia and efficient use of the-
atre time. There appears to be is no difference in neonatal outcome for the two techniques. Further studies are required to evaluate and confirm the find- ings presented here. We are currently prospectively comparing haemodynamic stability in spinal anaes- thesia for otherwise normal parturients presenting for
elective caesarean section with severely hypertensive pre-eclamptic patients.
REFERENCES
1. Writer D. Hypertensive Disorders. In: Chestnut D H. Obstetric Anesthesia Principals and Practice. St. Louis: Mosby, 1994; 868.
2. Hodgkinson R, Husain F J, Hayashi R H. Systemic and pulmonary blood pressure during Caesarean section in parturients with gestational hypertension. Can Anaesth Sot J 1980; 21: 3899394.
3. Benedetti T J, Chadwick H S, Easterling T. Preeclampsia. In: Bonica J J and McDonald J. Principals and Practice of Obstetric Analgesia and Anesthesia 2nd edn. Baltimore: Williams and Wilkins, 1995; 8555861.
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Hood D D, Boese R N. Epidural and spinal anesthesia for elective Cesarean section in severely pre-eclamptic parturients. Reg Anesth; 1992: lll(supp1): 35. Davey D A, Macgillivray I. The classification and definition of hypertensive disorders of pregnancy. Am J Obstet Gynecol 1988; 158: 892-898. Wallace D H, Leveno K J, Cunningham F G: Giesecke A H, Shearer V E, Sidawi J E. Randomized comparison of general and regional anesthesia for Cesarean delivery in pregnancies complicated by severe preeclampsia. Obstet Gynecol 1995; 86: 1933199. Purkis R E, Clark V, Sharwood-Smith G H. Pregnancy Induced Hypertension Audits 1992 and 1994. Scottish Clinical Audit Resource Centre Database. Mushambi M C, Halligan A W, Williamson K. Recent developments in the pathophysiology and management of preeclampsia. Br J Anaesth 1996; 76: 1333148. Morris N H, Eaton B M, Dekker G. Nitric oxide, the endothelium, pregnancy and preeclampsia. Br J Obstet Gynaecol 1996; 103: 415. Visser W, Wallenberg H C S. Central hemodynamic observations in untreated pre-eclamptic patients. Hypertension 1991; 17: 1072. Carlsson C. Cardiovascular changes in preeclampsia. Acta Obstet Gynec Stand. 1984; 118 supp: 12lll22. McCrae A, Wildsmith J A W. Prevention and treatment of hypotension during central neural block. Br J Anaesth 1993; 70: 672680. Howell P. Spinal anaesthesia in severe preeclampsia: time for appraisal, or time for caution? Editorial: International Journal of Obstetric Anesthesia 1998; 7: 217-219. Karinen J, Rasanen J, Alahuhta S, Jouppila R, Jouppila P. Maternal and uteroplacental haemodynamic state in pre- eclamptic patients during spinal anaesthesia for Caesarean section. Br J Anaesth 1996; 76: 616620. Clark V, McGrady E, Sugden C, Dickson J, McLeod G. Speed of onset of sensory block for elective extradural Caesarean section: choice of agent and temperature of injectate. Br J Anaesth 1994; 72: 221~ 223. Di Fazio C A, Carron H, Grosslight K R. Comparison of pH adjusted lidocaine solutions for epidural anesthesia. Anesth Analg 1986; 65: 760.-764. Russell I F. Levels of anaesthesia and intraoperative pain at caesarean section under regional block. International Journal of Obstetric Anesthesia 1995; 4: 71-77. Bourne T M, deMelo A E, Bastianpillai B A, May A E. A survey of how British obstetric anaesthetists test regional anaesthesia before Caesarean section. Anaesthesia 1997; 52: 896-913. Riley E T, Cohen S E, Macario A, Desai J B, Ratnet E F. Spinal versus epidural anesthesia for Cesarean section: a comparison of time efficiency, costs, charges and complications. Anesth Analg 1995; 80: 709-712. Peat R, Baigent C. Trials: the next 50 years. BMJ 1998; 317: 1170&l 171. Assali N S, Prytowsky H. Studies on autonomic blockade. Comparison between the effects of tetraethylammonium chloride (TEAC) and high selective spinal anesthesia on blood pressure of normal and toxemic pregnancy. J Clin Invest 1950; 29: 13541366. Moya F, Smith B. Spinal Anesthesia for Cesarean Section. JA MA 1962; 179: 6099614. Jackson R, Reid J A, Thorburn J. Volume preloading is not essential to prevent spinal induced hypotension at Caesarean section. Br J Anaesth 1995; 75: 2622265.
International Journal of Obstetric Anesthesia (2005) 14, 9–13� 2004 Elsevier Ltd. All rights reserved.doi:10.1016/j.ijoa.2004.08.002
11
ORIGINAL ARTICLE Digital thesis publication by permission of Elsevier Ltd 20Ephedrine requirements are reduced during spinalanaesthesia for caesarean section in preeclampsia
V. A. Clark, G. H. Sharwood-Smith, A. V. G. StewartThe Department of Anaesthesia, Simpson Centre for Reproductive Health, Edinburgh, UK
Background: Despite controversy over the haemodynamically safest blockade for caesarean section in women withsevere preeclampsia, an increasing number of anaesthetists now opt for spinal anaesthesia. In a previous study wefound that spinal compared to epidural anaesthesia offered an equally safe but more effective option for these patients.The current study was designed to compare the hypotension induced by spinal anaesthesia, as measured by ephedrinerequirement, between 20 normotensive and 20 severely preeclamptic but haemodynamically stabilised women.Method: Standardised spinal anaesthesia was instituted and ephedrine was given in boluses of 6 mg if the systolicpressure fell >20% from the baseline, or if the patient exhibited symptoms of hypotension.Results: The mean ephedrine requirement of the normotensive group (27.9 € 11.6 mg) was significantly greater(P < 0.01) than that of the preeclamptic group (16.4 € 15.0 mg).Conclusion: This suggests that the hypotension induced by spinal anaesthesia in women with severe but haemody-namically stabilised preeclampsia, is less than that of normotensive patients.� 2004 Elsevier Ltd. All rights reserved.
Keywords: Anaesthesia; Preeclampsia; Obstetric anaesthesia; Spinal anaesthesia
INTRODUCTION
The choice of general or regional anaesthesia for pa-tients with severe preeclampsia continues to attract de-bate. Epidural anaesthesia has become generallyacceptable but the risk of hypotension following spinalanaesthesia remains a focus for concern.1–3 However,this view has not been supported by clinical studies.4–7
A previous prospective study in our centre comparedepidural versus spinal anaesthesia in severely hyperten-sive preeclamptic patients.8 We found that profoundhypotension did not occur with either technique and thatspinal anaesthesia was not only more time-efficient butalso offered more effective and reliable anaesthesia. Pre-
Accepted August 2004
Data used in this article were presented, in part, at the ObstetricAnaesthetists’ Association Meeting in Winchester, UK on 11th May2000.
V.A. Clark MB ChB FRCA, G.H. Sharwood-Smith MB ChB FRCA,A.V.G. Stewart MB ChB DA FRCA, Simpson Centre forReproductive Health, Edinburgh EH16 4SA, Scotland, UK.
Correspondence to: Dr. Geoffrey Sharwood-Smith,Consultant Anaesthetist, Simpson Centre for Reproductive Health,Royal Infirmary of Edinburgh, EH16 4SA, UK.Tel.: +0044 131 242 3151; fax: +0044 131 242 3138.E-mail: [email protected].
9
eclampsia appeared to confer a condition of relative hae-modynamic stability following spinal and epiduralanaesthesia. We therefore designed this study to evalu-ate this hypothesis further, by measuring ephedrinerequirement following spinal anaesthesia in severelyhypertensive preeclamptic patients versus a normoten-sive control group presenting for caesarean section.
METHODS
Following ethics approval we obtained written informedconsent from 40 non-labouring parturients: 20 womenwere normotensive and 20 had severe preeclampsiarequiring antihypertensive therapy. All study patientswere scheduled for elective or urgent but not emergencydelivery. In the preeclamptic group obstetric medicalstaff made the diagnosis of preeclampsia following theonset of hypertension and proteinuria after 20 weeks’gestation using standard criteria.9 Severely preeclampticpatients were recruited on the basis of a sustained pre-treatment diastolic blood pressure >110 mmHg. Thesepreeclamptic women were stabilised with nifedipine,labetalol or methyldopa alone or in combination as indi-cated according to obstetric preference within our unitprotocol. The study was completed before magnesium
10 International Journal of Obstetric Anesthesia
sulphate was added to our unit preeclampsia protocol.The preeclamptic patients were recruited over a 20-month period as they presented to the investigators.The control patients were recruited in parallel until 20patients had been studied. Randomisation was notappropriate due to the study design. Any patient whohad an eclamptic fit, a coagulopathy, declined regionalanaesthesia, was <153 or >170 cm tall or >100 kg inweight, was excluded from the study. Written informedconsent was obtained.
Preoperatively patients were given ranitidine either ina dose of 150 mg orally or 50 mg i.m. or i.v. accordingto the urgency of the delivery; 0.3 M sodium citrate 30mL was administered orally in the anaesthetic room.Baseline systolic pressure was measured as the meanof three readings taken 5 min after arrival in the anaes-thetic room and before instituting any invasive pro-cedures. A systolic pressure 20% below the baselinewas set as the level for administration of intravenousephedrine.
The spinal anaesthetic was sited in the left lateral po-sition with a 24-gauge Sprotte needle at the second orthird lumbar interspace. Hyperbaric 0.5% bupivacaine2.5 mL and fentanyl 12.5 lg were injected into the sub-arachnoid space. The patient was then turned supinewith a wedge placed under the right buttock to preventaortocaval compression. After 5 min the block wastested for analgesia to pinprick with a blunt needle.When analgesia was demonstrated to T5 bilaterally(T5 being the first unblocked segment), surgeryproceeded.
Fluid management up to the completion of surgerywas standardised for both groups in the study. Beforesiting the spinal anaesthetic, a large bore i.v. cannulawas inserted and an infusion of Hartmann’s solutionwas started. The drip rate was adjusted so that by theend of instituting the spinal anaesthetic 250 mL of thesolution had been infused. Intra-operative blood losswas replaced with Hartmann’s solution or blood asjudged clinically appropriate. The restricted intravenouspreload for the preeclamptic group is required by ourunit protocol; we also applied it to the control groupsince a larger intravenous preload has not been foundto reduce the incidence of hypotension after spinalanaesthesia in normal obstetric patients.10 Postopera-tively the preeclamptic patients were restricted to 80mL/h plus losses.
Patient monitoring included electrocardiography,pulse oximetry and automated non-invasive blood pres-sure recordings (Datex Cardiocap 2 monitor) at 2-minintervals. Oxygen was given at 4 L/min via a Hudsonmask until delivery when synthetic oxytocin (Syntoci-non), 10 units, was given i.v. (the study was completedbefore publication of the recent recommendation thatthis Syntocinon bolus be limited to 5 units 11). If pain
was felt during surgery, Entonox (50:50 mixture of ni-trous oxide and oxygen) and morphine were given as re-quired. If the initial block was inadequate (failed toreach the specified height of T5), the patient was to bewithdrawn from the study and an appropriate alternativeanaesthetic administered. Ephedrine in 6-mg incrementswas given at 2-min intervals if the systolic blood pres-sure fell below 20% of the baseline or if the patientexhibited symptoms associated with hypotension (nau-sea or vomiting). The presence of nausea, vomiting orbradycardia was recorded. A paediatrician recorded 1-and 5-min Apgar scores. Postoperatively mothers whohad preeclampsia were monitored in our high depen-dency unit for a minimum of 24 h. Postoperatively, allpatients received i.v. morphine by patient-controlledanalgesia (PCA) for 24 h.
Results are presented as mean € standard deviation,with 95% confidence intervals. Power analysis basedon published research indicated that 20 study and 20control group patients would be required for a 90%power to detect a significant difference of 11 mg inephedrine dose between the groups assuming a commonstandard deviation of 11.6 mg at the P < 0.05 signifi-cance level. GraphPad Prism 3 statistical software wasused; ephedrine requirement was analysed using theMann-Whitney test.
RESULTS
Of the 40 women recruited no patient had to be excludedfrom the study. There were no demographic differencesbetween the two groups apart from the earlier gesta-tional age of preeclamptic patients (Table 1). Thepreeclamptic patients were all stabilised on antihyper-tensive drugs and had no clinical evidence of pulmonaryoedema; SpO2 measurements were all within the normalrange. The mean ephedrine requirement of the normo-tensive group (27.9 € 11.6 mg, 95% CI 22.5, 33.3) wassignificantly greater (P < 0.01) than that in the pre-eclamptic group (16.35 € 15.0 mg, 95% CI 9.3, 23.4)(Fig. 1).
DISCUSSION
In 1950 Assali and Prystowsky demonstrated that se-verely hypertensive preeclamptic patients were resistantto the haemodynamic effect of sympathetic blockade;they used both spinal anaesthesia and ganglionic block-ade.12 Despite this early finding there is a persistingdogma to the effect that these patients may become se-verely hypotensive following spinal anaesthesia forcaesarean section. Wallace et al. challenged this viewwith a prospective study in which 80 women were
Table 1. Patient characteristics, ephedrine usage, incidence of nausea and vomiting, blood pressure and bradycardia data, neonatal Apgarscores, antihypertensive therapy and indications for caesarean delivery
Preeclamptics (n = 20) Normotensives (n = 20)
Age (years) 30.9 (6.2) 29.7 (4.7)Height (cm) 160 (63) 160 (44)Gestation (weeks) 34.9 (3.9) 39.4 (1.2)Pre-spinal systolic blood pressure (mmHg) 147 (18.4)** 123 (10.9)**
Ephedrine requirement (mg) 16.4 (15.0)* 27.9 (11.6)*
Ephedrine not required (n) 3 0Nausea 8 12Vomiting 1 6Bradycardia <60 beats/min 1 4Apgar scores <7
1 min 5 05 min 1 0
Labetalol and Nifedipine 8 0Labetalol 7 0Methyldopa 2 0Nifedepine 2 0Methyldopa and Nifedipine 1 0Indications for caesarean delivery
Preeclampsia 20 0Previous caesarean delivery 0 7Breech presentation 0 11Unstable lie 0 1Fractured pelvis 0 1
Data are mean (SD) or numbers of patients.* P < 0.01.** P < 0.001.
Fig. 1 Dot plots showing individual ephedrine requirements for thepreeclamptic and normotensive control groups. The mean ephedrinerequirement for the preeclamptic group was 16.4 mg and for thenormotensive group it was 27.9 mg.
Ephedrine dose during spinal anaesthesia in preeclampsia 11
randomised to general, epidural or combined spinal/epidural anesthesia.7 Hood and Curry followed with aretrospective review of 103 spinal and 35 epidural ana-esthetics administered to severely preeclamptic pa-tients.6 They found similar blood pressure changes andephedrine requirements in both groups, suggesting that
severe hypotension was not a problem. Further studieshave confirmed these findings.4,5 Despite these studies,theoretical reasons for maintaining a cautious approachto the safety of spinal anaesthesia have been advancedin two editorials and a standard textbook.1–3 We origi-nally published a prospective study in which we usedephedrine requirement as an index of haemodynamicstability during epidural versus spinal anesthesia.8 Wefound that blood pressure could be safely controlled withboth techniques but the epidural group so consistentlydemonstrated inadequate analgesia that the study sizewas limited by ethical concerns. Our methodology con-trasted in important ways with that used by the otherinvestigators. In both the study reported here and alsoour previous one, patients were haemodynamically sta-bilised before anaesthesia. Additionally, preoperativei.v. fluid administration was standardised. Also, ratherthan observing any resultant hypotensive episodes wetook a pro-active approach in line with our unit protocol.The intention was to control systolic blood pressurewithin our predetermined safe limits. We used systolicrather than diastolic or mean arterial pressure in linewith normal clinical practice during obstetric spinalanaesthesia. The rationale for this is as follows. Estima-tion of mean arterial pressure depends on intermittentmanual or automated systolic and diastolic blood pres-sure measurements; diastolic blood pressure measuredin this way is subject to uncertainty since both Korotkov4 and 5 recordings may be unreliable in pregnancy.13
Invasive monitoring is not ethically justified in
12 International Journal of Obstetric Anesthesia
stabilised and otherwise uncomplicated patients; non-invasive continuous blood pressure measurement pre-sents technical difficulties in obstetric patients.
Symptoms of nausea and vomiting are arguably amore sensitive indicator of rapid-onset hypotension thannon-invasive blood pressure measurements. In this studyonly one preeclamptic patient experienced vomiting incontrast to six in the normotensive group (Table 1).
It is useful to review the cardiovascular changes thatmight account for the significantly reduced ephedrinerequirements we found in the preeclamptic group. Itcould be argued that the lower gestational age of pre-eclamptic patients at delivery would result in a reduceddegree of caval compression. Two studies oppose thistheory. There was no decrease in cardiac output in 128preeclamptic subjects studied in the supine position,14
conversely decreased cardiac output has been observedat only 20-24 weeks’ gestation in normal pregnancies.15
A more convincing explanation is to be found in theoestrogen-dependant vascular changes of normal preg-nancy. From the tenth week of gestation there is adecrease in endogenous pressor responsiveness (espe-cially to angiotensin II) due to an endothelium-depen-dant alteration of vascular smooth muscle, anincreased synthesis of vasodilator prostaglandins andan increased rate of nitric oxide synthesis leading to adecrease in vasodilator tone.16–18 The net effect is a de-crease in peripheral vascular resistance beginning inearly pregnancy. Consequently, in normal pregnancythere appears to be an increased dependence on sympa-thetic vasoconstriction for the control of vascular tone;together with the problem of supine caval compressionthis probably explains the profound falls in blood pres-sure sometimes seen following spinal anaesthesia inotherwise uncomplicated obstetric patients. By contrasta consistent feature of preeclampsia is damage to thematernal endothelial vascular mechanism;19 conse-quently there may be a paradoxical resistance to hypo-tension following sympathetic blockade.
Although the preeclamptic group demonstrated a rel-atively reduced hypotensive response, six individualsmore closely resembled the normotensive control group(Fig. 1), with the requirement for more than 18 mgephedrine being an apparent separator. It was not possi-ble to define any other clinical characteristics, such ashypotensive therapy or pre-existing hypertension, spe-cific to this group and the number was too small foranalysis. This finding may simply represent the hetero-geneous pathology of preeclampsia.
In summary, we have studied a group of severelyhypertensive preeclamptic women who had been stabi-lised with antihypertensive drugs before receiving spinalanaesthesia for caesarean section. This group requiredsignificantly less ephedrine to maintain systolic bloodpressure within predetermined limits than an uncompli-
cated obstetric control group. In terms of ephedrinerequirement the preeclamptic group was more haemody-namically stable than the normal control group. Thisstudy adds to recent evidence suggesting that hyperten-sive but stabilised patients with severe preeclampsiawho have no other contraindication to spinal anaesthesiashould not be denied this effective form of anaesthesiafor operative delivery.
ACKNOWLEDGEMENT
Dr. Bernhard Heidemann gave valuable advice on data analysis.
REFERENCES
1. Santos A C. Spinal anesthesia in severely preeclamptic women:when is it safe? Anesthesiology 1999; 90: 1252–1254.
2. Howell P. Spinal anesthesia in severe preeclampsia:time forreappraisal, or time for caution. Int J Obstet Anesth 1998; 7:217–219.
3. Gambling D R, Writer D. Hypertensive disorders. In:Chestnut D H, ed. Obstetric Anesthesia: Principles and Practice.2nd Ed. St Louis: Mosby; 1999; 903–909.
4. Aya A G, Mangin R, Vialles N, et al. Patients with severepreeclampsia experience less hypotension during spinal anesthesiafor elective cesarean delivery than healthy parturients: aprospective cohort comparison. Anesth Analg 2003; 97: 867–872.
5. Chiu I U, Mansor M, Ng K P, Chan Y K. Retrospective review ofspinal versus epidural anaesthesia for caesarean section in pre-eclamptic patients. Int J Obstet Anesth 2003; 12: 17–23.
6. Hood D D, Curry R. Spinal versus epidural anesthesia for cesareansection in severely preeclamptic patients: a retrospective survey.Anesthesiology 1999; 90: 1276–1282.
7. Wallace D H, Leveno K J, Cunningham F G, Giesecke A H,Shearer V E, Sidawi J E. Randomized comparison of general andregional anesthesia for cesarean delivery in pregnanciescomplicated by severe preeclampsia. Obstet Gynecol 1995; 86:193–199.
8. Sharwood-Smith G H, Clark V A, Watson E. Regional anaesthesiafor caesarean section in severe preeclampsia: spinal anaesthesia isthe preferred choice. Int J Obstet Anesth 1999; 8: 85–89.
9. Davey D A, Macgillivary I. The classification and definition ofhypertensive disorders of pregnancy. Am J Obstet Gynecol 1988;158: 892–898.
10. Jackson R, Reid J A, Thorburn J. Volume preloading is notessential to prevent spinal-induced hypotension at caesareansection. Br J Anaesth 1995; 75: 262–265.
11. Why Mothers Die 1997–1999. The fifth report of the ConfidentialEnquiries into Maternal Deaths in the United Kingdom. London:TSO, 1999.
12. Assali N S, Prystowski H. Studies on autonomic blockade.Comparison between the effects of tetraethylammonium chlorideTEAC and high selective spinal anesthesia on blood pressure ofnormal and toxemic pregnancy. J Clin Invest 1950; 29: 1354–1365.
13. Shennan A, Gupta M, Halligan A, Taylor D J, De Swiet M. Lack ofreproducibility in pregnancy of Korotkoff phase IV as measured bymercury sphygmomanometry. Lancet 1996; 347: 139–142.
14. Visser W, Wallenburg H C. Central hemodynamic observations inuntreated preeclamptic patients. Hypertension 1991; 17:1072–1077.
15. Ueland K, Novy M J, Peterson E N, Metcalfe J. Maternalcardiovascular dynamics. IV. The influence of gestational age onthe maternal cardiovascular response to posture and exercise. Am JObstet Gynecol 1969; 104: 856–864.
16. Whalley P J, Everett R B, Gant N F, Cox K, MacDonald P C.Pressor responsiveness to angiotensin II in hospitalized
Ephedrine dose during spinal anaesthesia in preeclampsia 13
primigravid women with pregnancy-induced hypertension. Am JObstet Gynecol 1983; 145: 481–483.
17. Boccardo P, Soregaroli M, Aiello S, et al. Systemic andfetal-maternal nitric oxide synthesis in normal pregnancyand pre-eclampsia. Br J Obstet Gynaecol 1996; 103:879–886.
18. Cockell A P, Poston L. Flow-mediated vasodilatation is enhancedin normal pregnancy but reduced in preeclampsia. Hypertension1997; 30: 247–251.
19. Redman C W, Sacks G P, Sargent I L. Preeclampsia: an excessivematernal inflammatory response to pregnancy. Am J ObstetGynecol 1999; 180: 499–506.
Bruce J, Sharwood-Smith G, Drummond G. Pulse transit time: a new approach to
haemodynamic monitoring in obstetric spinal anaesthesia. Int J Obstet Anaesth 2002; 11,
Supplement 1, 1-38
Pulse transit time: a new approach to haemodynamic monitoring in obstetric spinal anaesthesia
J Bruce, G Sharwood-Smith and G Drummond
Department of Anaesthesia and Simpson Memorial Maternity Pavilion, Edinburgh, Scotland
Introduction: Hypotension is a frequent complication of obstetric spinal anaesthesia. Slow response of non-
invasive blood pressure measurements or using symptoms such as nausea and vomiting can delay treatment, but
early use of vasopressors may be unnecessary. Pulse Transit Time (PTT) is obtained from routine non-invasive
monitors, and shows beat-to-beat vascular changes during regional anaesthesia.1
Method: After ethical committee approval we studied 62 patients scheduled for elective or urgent Caesarean
Section. Patients with major medical complications or pre-eclampsia were excluded. Spinal anaesthesia was
with hyperbaric bupivacaine 0.5% and diamorphine. A Datex Cardiocap provided non-invasive blood pressure,
ECG, and plethysmograph signals for analysis. We recorded the time between the ECG R wave and the
maximum rate of change of the optical plethysmograph at the second toe by analogue computer. Values given
are median (quartiles).
Results: Data from 58 patients were analysed. Maximal changes in PTT occurred 2.39 (1.4,3.4) minutes after
spinal anaesthetic. Changes in PTT and mean arterial pressure (MAP) were significantly related ( r2 = 0.55, P <
0.0001). Measurements of the second value of PTT were taken 0.2 (-0.2,1.0) min before the measurements of
MAP.
0 25 50 75 100 125 1500
250
500
750
MAP (mm Hg)
PT
T (
msec)
Figure 1: Individual values of PTT and MAP before (small squares), and following (large circles) spinal
anaesthesia.
Conclusions: PTT can be derived from standard non-invasive monitors and gives early information on the
vascular effects of spinal anaesthesia. PTT is worthy of further investigation in this context. References
1. Babchenko A, Davidson E, Adler D, Ginosar Y, Kurz V, Nitzan M. Increase in pulse transit time to the foot after epidural anaesthesia
treatment. Med Biol Eng Comput 2000; 38: 674-9.
Original abstract presented at the OAA congress 2002and published in the affiliated journal as cited. The datalater published in a full peer reviewed article on page 66.
Sharwood-Smith G, Drummond G, Bruce J. Pulse transit time confirms altered haemodynamic response
to spinal anaesthesia in pregnancy induced hypertension. Hypertension in Pregnancy 2002; 21 suppl 1: 31
Pulse Transit Time Confirms Altered Haemodynamic Response to Spinal Anaesthesia in Pregnancy Induced
Hypertension.
G. Sharwood-Smith(1,2), G. Drummond(2), J. Bruce(2) Simpson Memorial Maternity Pavilion(1), Department of
Anaesthesia(2), Royal Infirmary, Edinburgh EH3 9YW, Scotland, United Kingdom.
Background: Despite evidence to the contrary, spinal anaesthesia in patients with Pregnancy Induced Hypertension (PIH) is
considered likely to cause severe hypotension. Pulse transit time (PTT) gives a non invasive beat to beat measurement of
vascular changes.
Methods: After ethical approval, we studied 15 patients with PIH and 58 control patients having elective or urgent
Caesarean section. Spinal anaesthesia was with hyperbaric bupivacaine 0.5% and diamorphine. A Datex Cardiocap provided
non-invasive blood pressure, ECG, and plethysmograph signals for analysis. We recorded the time between the ECG R
wave and the maximum rate of change of the optical plethysmograph at the second toe by analogue computer. Values given
are median (quartiles).
Results: Mean arterial pressure (MAP) before spinal anaesthesia was 99 (91,104) mm Hg in control and 115(104,119) mm
Hg in the PIH patients. After spinal anesthesia, MAP decreased by 18 (5, 33) mm Hg and 22 (11,29) mm Hg in control and
PIH patients respectively. Before anaesthesia, PTT was similar in the two groups (Control, 390 (346,417) mSec and PIH,
353 (325,383) mSec). PTT increased significantly more quickly in the control patients (32 (14,56) mSec/min) than in the
patients with PIH (7 (6,18) mSec/min). (P < 0.01, Mann Whitney U test)
Conclusions: PTT changes can be used to study PIH. The slow change of
PTT after spinal anaesthesia suggests that arteries relax more slowly in PIH.
Funding: This study was supported by a grant from the Obstetric Anaesthetists’ Association (UK)
Original abstract presented at the ISSHP Congress Toronto 2002and published in the affiliated Journal 'Hypertension in Pregnancy'.The data later published in a full peer reviewed article on page 66.
PULS
E TRA
NSIT
TIME C
ONFIR
MS AL
TERE
D RES
PONS
E TO S
PINAL
ANAE
STHE
SIA IN
PREG
NANC
Y IND
UCED
HYPE
RTEN
SION
G Sha
rwoo
d-Smi
th, G
Drum
mond
, J Br
uce
Simp
son C
entre
for R
eprod
uctiv
e Hea
lth an
d Dep
artme
nt of
Anae
sthes
ia, Ro
yal In
firma
ry, Ed
inburg
h EH1
6 4SA
, Sco
tland
, Unit
ed Kin
gdom
Bac
kgro
und
Des
pite
con
trary
evi
denc
e, 1 s
pina
l ana
esth
esia
in p
atie
nts
with
pre
gnan
cy
indu
ced
hype
rtens
ion
(PIH
) is
still
con
side
red
a po
tent
ial c
ause
of s
ever
e hy
pote
nsio
n. 2
The
vess
el ch
ange
s in
PIH
giv
e a
phys
iolo
gica
l bas
is fo
r rec
ent
clin
ical
find
ings
of r
esis
tanc
e to
hyp
oten
sion
follo
win
g sp
inal
ana
esth
esia
: en
doth
elia
l da
mag
e im
pairs
the
nitr
ic o
xide
and
pro
stag
land
in m
edia
ted
vaso
dila
tatio
n of
nor
mal
pre
gnan
cy -
so b
lood
pre
ssur
e in
PIH
may
be
less
de
pend
ant o
n sy
mpa
thet
ic to
ne. W
e se
t out
to in
vest
igat
e pu
lse
trans
it tim
e (P
TT) a
s a
mea
ns o
f stu
dyin
g th
ese
chan
ges.
Met
hods
Ethi
cal a
ppro
val w
as o
btai
ned
- car
diac
dis
ease
, dia
bete
s an
d ot
her c
ause
s of
hyp
erte
nsio
n w
ere
excl
uded
- n
on-in
vasi
ve b
lood
pre
ssur
e, E
CG
and
pl
ethy
smog
raph
sig
nals
wer
e ob
tain
ed fr
om a
Dat
ex C
ardi
ocap
mon
itor -
th
e tim
e be
twee
n th
e EC
G R
wav
e an
d th
e m
axim
um ra
te o
f cha
nge
of th
e op
tical
ple
thys
mog
raph
at
the
seco
nd t
oe w
as m
easu
red
by a
nalo
gue
com
pute
r - s
pina
l ana
esth
esia
was
with
2.5
-2.7
ml h
yper
baric
bup
ivac
aine
0.
5% +
300
-400
mcg
dia
mor
phin
e - a
blo
ck w
as e
stab
lishe
d to
abo
ve th
e T6
der
mat
ome
bila
tera
lly in
all
subj
ects
- P
IH p
atie
nts
wer
e tre
ated
with
ni
fedi
pine
and
/or l
abet
alol
acc
ordi
ng to
our
uni
t pro
toco
l
Res
ults
We
recr
uite
d 82
pat
ient
s for
an
obse
rvat
iona
l stu
dy, 7
8 pr
ovid
ed a
dequ
ate
data
. Maj
or m
edic
al c
ondi
tions
wer
e pr
esen
t in
5. W
e pr
esen
t dat
a fro
m
58 c
ontro
l pat
ient
s an
d 15
pat
ient
s w
ith P
IH
C
ontro
l
P
IH
Age
32
(30,
34)
31 (3
0, 3
4)
Ges
tatio
n (w
eeks
)
39 (3
9)
3
6 (3
3, 3
8) He
ight
(cm
)
62
(158
,167
1
62 (1
62, 1
68)
Wei
ght (
kg)
6
9.5
(61,
76
7
2 (6
6, 7
9)
PTT
incr
ease
d si
gnifi
cant
ly m
ore
quic
kly
in th
e co
ntro
l pat
ient
s (3
2 (1
4,56
) mSe
c/m
in) t
han
in th
e PI
H p
atie
nts
(7(6
,18)
mSe
c/m
in).
(P<0
.01
Man
n W
hitn
ey U
test
)
Puls
e Tr
ansi
t Tim
e....
.. Is
the
time
take
n fo
r the
arte
rial p
ress
ure
wav
e to
tra
vel b
etw
een
the
aorti
c va
lve
and
the
perip
hery
- it
can
be m
easu
red
non-
inva
sive
ly -
it ha
s be
en u
sed
to in
vest
igat
e ch
ange
s in
arte
rial s
tiffn
ess
due
to s
ympa
thet
ic b
lock
ade
in e
pidu
ral a
naes
thes
ia. 3
Con
clus
ions
P
TT c
hang
es c
an b
e u
sed
to s
tudy
PIH
T
he s
low
cha
nge
of P
TT s
ugge
sts
that
arte
ries
rela
x m
ore
slo
wly
afte
r sp
inal
ana
esth
esia
in
PIH
T
he re
lativ
e sa
fety
of s
pina
l ana
esth
esia
in P
IH is
con
firm
ed.
Ref
eren
ces
1.
Sha
rwo
od
-Sm
ith G
H, C
lark
V, W
ats
on
E. R
eg
iona
l ane
sthe
sia fo
r ca
esa
rea
n se
ctio
n in
se
vere
pre
ec
lam
psia
: sp
ina
l ane
sthe
sia is
the
pre
ferre
d c
hoic
e. I
nte
rna
tiona
l Jo
urna
l of O
bst
etri
c A
nest
hesia
199
9;8:
85-8
9. 2.
Sa
nto
s AC
. Sp
ina
l ane
sthe
sia in
se
vere
ly p
ree
cla
mp
tic w
om
en:
whe
n is
it sa
fe?
[ed
itoria
l; c
om
me
nt].
Ane
sthe
siolo
gy
1999
; 90:
1252
-125
4.
3.
Bab
cha
nko
A, D
avi
dso
n E,
Ad
ler D
, Gin
osa
r V, K
urz
V, N
itza
n M
. Inc
rea
se in
pul
se tr
ans
it tim
e to
the
foo
t afte
r ep
idur
al a
nae
sthe
sia tr
ea
tme
nt. M
ed
& B
iol E
ng a
nd C
om
put
ing
200
0: 6
74-9
.
Thesis page 65 © G Sharwood-Smith, G Drummond and J Bruce
British Journal of Anaesthesia 96 (1): 100–5 (2006)
doi:10.1093/bja/aei266 Advance Access publication October 28, 2005
Assessment of pulse transit time to indicate cardiovascularchanges during obstetric spinal anaesthesiay
G. Sharwood-Smith*, J. Bruce and G. Drummond
Department of Anaesthesia, Critical Care and Pain Medicine, Royal Infirmary of Edinburgh,
Edinburgh EH16 4SU, UK
*Corresponding author. E-mail: [email protected]
Background. Pulse transit time (PTT) measurement may provide rapidly available beat-to-beat
cardiovascular information when conditions change quickly and routine invasive arterial pressure
measurement is not justified, for example during obstetric spinal anaesthesia.
Method. We obtained ethics approval for an observational study of PTT during the onset of
spinal anaesthesia in patients having elective or urgent Caesarean section. PTT was measured
as the difference in time between the peak of the ECG R wave and the upstroke of the toe
plethysmograph. Arterial pressure was measured by non-invasive sphygmomanometry.
Results. We analysed data from 58 normotensive patients and 15 patients with pregnancy-
induced hypertension (PIH). PTT increased with the onset of spinal anaesthesia as arterial pres-
sure decreased. An increase of 20% in PTT was 74% sensitive and 70% specific in indicating
a decrease in mean arterial pressure of more than 10%. Changes in PTT were related to changes
in mean arterial pressure (r2=0.55, P<0.0001). Arterial pressure changes were greater and PTT
increased significantly more quickly in the normotensive patients than in the patients with
hypertension [median, quartiles: 32 (14, 56) ms min�1 compared with 7 (6, 18) ms min�1;
P<0.01, Mann–Whitney U-test]. However, the relationship between PTT and arterial pressure
was similar for the normotensive patients and the patients with PIH.
Conclusion. PTT measurement gave a beat-to-beat indication of arterial pressure during spinal
anaesthesia, and could be developed to allow prediction of the onset of hypotension.
Br J Anaesth 2006; 96: 100–5
Keywords: anaesthesia, obstetric; anaesthetic techniques, regional, spinal; cardiovascular
system; monitoring, pulse transit time; pregnancy
Accepted for publication: September 24, 2005
In clinical conditions, arterial pressure may change so
quickly that intermittent non-invasive measurements may
be too slow and inaccurate to allow early detection and
prompt treatment, especially in obese subjects. However,
routine invasive measurement may be inappropriate, for
example in obstetric spinal anaesthesia, where hypotension
is the most frequent complication and poses risks to both
mother and foetus. In conscious subjects, arm movement can
delay the display of an arterial pressure reading through two
or three measurement cycles, often at a time when changes
may be considerable. An additional non-invasive measure-
ment that could give early warning of arterial pressure
change would be useful clinically.
Pulse transit time (PTT) measurement offers beat-to-beat
cardiovascular information.1 Such measurements have been
used previously to infer changes in autonomic activity2 and
arterial pressure.3 PTT, measured as the interval from the
ECG R wave to the pulse plethysmograph upstroke, was
used recently to assess cardiovascular responses to anaes-
thesia and intubation.4 Both the ECG and the plethysmo-
graph wave can be obtained from standard monitoring
equipment. We used a custom-built analogue device to
acquire automatically the interval between the ECG R
wave and the pulse plethysmograph upstroke.
PTT is of clinical interest as an index of arterial stiffness
and hence of arterial pressure,3 5 since arterial stiffness
increases as arterial pressure increases.6–8 However, other
factors may affect arterial stiffness. For example, recent
studies suggest that hypotension following spinal
� The Board of Management and Trustees of the British Journal of Anaesthesia 2005. All rights reserved. For Permissions, please e-mail: [email protected]
yData from this study were presented in part at the Obstetric Anaes-
thetists Association Meeting at Nottingham, UK, on May 10, 2002 and
at the 13th World Congress of the International Society for the Study of
Hypertension in Pregnancy at Toronto, Canada, on June 2, 2002.
Thesis page 66
Digital thesis publication by permission of Oxford University Press 2011
anaesthesia is less likely in patients with pregnancy-induced
hypertension (PIH) than in normotensive patients.9 Changes
in PTT following spinal anaesthesia may indicate differ-
ences in arterial stiffness in these patients.
The prime aim of this study was to observe PTT in a
clinical scenario where sudden onset of hypotension is
relatively frequent, and assess its value for predicting
such changes. A secondary aim was to compare the
responses of patients with and without PIH.
Methods
The local ethics committee approved collection and record-
ing of data from routine cardiovascular monitoring devices,
but not the modification of routine management in any other
way. We obtained informed verbal consent for the data
collection. We recorded PTT during the onset of spinal
anaesthesia in non-labouring women having Caesarean sec-
tion for routine elective or urgent indications. Patients were
recruited as they presented over a 6-month period; of these,
74 were normotensive. Eighteen patients had severe PIH,
defined using standard criteria10 as hypertension which
developed after 20 weeks of gestation and required anti-
hypertensive medication with nifedipine, labetalol or
methyldopa, singly or in combination. We included patients
with or without proteinuria. We undertook this study before
our unit introduced i.v. magnesium sulphate treatment for
severe PIH.
The values were obtained from before the spinal anaes-
thetic to the time the patient was ready for surgery. Vaso-
pressor or vagolytic drugs were given by the clinician
managing the anaesthesia, according to normal practice,
in response to changes in arterial pressure, heart rate, or
the onset of symptoms suggestive of hypotension, such as
dizziness, nausea or vomiting. Some of these clinicians did
not routinely give vasopressor agents prophylactically,
others did, and some gave them occasionally.
Patients were placed in a supine wedged position and an
infusion of Hartmann’s solution was started. ECG monitor-
ing and an automated arterial pressure (NIBP) recording cuff
were applied (Cardiocap 2; Datex). The baseline arterial
pressure was recorded as the mean of three measurements
taken at 2-min intervals. An oximeter probe was placed on
the second toe of the left foot. Spinal anaesthesia was then
administered with the patient in either the sitting or left
lateral position. A 24 gauge Sprotte needle was used to
give between 2.5 and 2.7 ml of hyperbaric bupivacaine
0.5% with diamorphine 0.3 or 0.4 mg according to the
anaesthetists’ preference. The patient was then returned to
the wedged supine position. The time was recorded, and the
events that were marked electronically included the follow-
ing: the connection of monitoring equipment; the initial
change of position for the spinal; the return to a wedged
supine position; the administration of vasopressor or other
i.v. drugs; and the transfer of the patient to the operating
theatre. IV fluids given before spinal anaesthesia and the
total given over the study period were recorded. Heart rate
and NIBP were recorded at 2-min intervals. The ECG and
photoplethysmograph signals from the analogue output of
the Cardiocap monitor were transferred to a purpose-built
analogue computer constructed by Leiden University. This
computed the time between the peak of the ECG R wave and
the maximum rate of the plethysmograph wave upswing.
The time intervals and digital signals from the Datex mon-
itor were recorded in digital form on a Satellite Pro 4300
(Toshiba) laptop computer.
Before data analysis, spurious ECG and photoplethysmo-
graph signals generated by patient movement were removed.
These artefacts were defined using an Excel function (Excel
version 9.0, 1999; Microsoft, Redmond, WA, USA) as val-
ues that were 20% less or greater than the rolling mean
PTT, and were filtered from the data before analysis.
Statistical analysis was with GraphPad Prism version 3.02
and Analyse-It software for Excel, version 1.71 (Analyse-it
Software, Leeds, UK). Data are presented as medians
(quartile values) unless stated otherwise.
Results
Ninety-two patients were studied; we obtained data suitable
for analysis from 58 normotensive patients and 15 with PIH.
There were no obvious systematic differences in the reasons
for exclusion between the two groups of patients (Table 1).
The two groups were similar in respect of height and weight,
but, as might be expected, heart rate was less, arterial pres-
sure was greater and gestational age was less in the patients
with PIH (Table 2). Before the spinal anaesthetic, nor-
motensive patients were given 400 (300, 500) ml of
Hartmann’s solution and the patients with PIH received
150 (100, 225) ml. The dose of bupivacaine was 13
(12.5, 13.5) mg in both the normotensive and the hypertens-
ive patients. Most patients received diamorphine 300 mg, but
nine were given 400 mg. Ephedrine had to be given to 46 of
the normotensive patients and three of the patients with PIH
(P<0.001); other vasopressor and vagolytic agents
(phenylephrine, atropine and glycopyrollate) were also
used more frequently in the normotensive patients.
Data from five patients were not analysed because
vasopressor drugs were given prophylactically by personal
preference of the anaesthetist immediately after spinal
Table 1 Reasons for exclusion from analysis
Normotensive PIH
Total number before exclusions 74 18
Reasons for exclusion
Inadequate data 9 1
Vasopressor given prophylactically 5 0
Computer failure 1 0
Conversion to general anaesthetic 1 0
Insulin-dependent diabetes 0 1
Essential hypertension 0 1
Number of patients analysed 58 15
Pulse transit time during obstetric spinal anaesthesia
101
Thesis page 67
anaesthesia and before PTT and arterial pressure recordings
could be obtained. A standardized format of clinical practice
was not imposed in this observational study. In 10 patients,
technical problems with recording either PTT or arterial
pressure yielded insufficient data for analysis.
Mean arterial pressure (MAP) before spinal anaesthesia
was 99 (91, 104) mm Hg in the normotensive patients and
115 (104, 119) mm Hg in patients with PIH. With the onset
of spinal anaesthesia, MAP decreased by 18 (5, 33) and
22 (11, 29) mm Hg in normotensive and PIH patients
respectively.
Patient movement and repositioning after carrying out the
block disturbed the ECG and plethysmograph signals, and
could cause spurious PTT values. These were less than 3%
of the total values obtained. Before anaesthesia, PTT was
significantly less in the patients with PIH: 353 (325, 383) ms
(P<0.05) compared with 390 (346, 417) ms in the nor-
motensive group (P<0.05). PTT changed during the onset
of spinal anaesthesia (Fig. 1) by 24% in the normotensive
group and 21% in the PIH group. The greatest change in PTT
occurred 2.4 (1.4, 3.4) min after spinal anaesthetic in the
normotensive group and 5.0 (3.2, 7.7) min after spinal anaes-
thetic in the hypertensive group. Thus, PTT increased more
rapidly in the normotensive patients [32 (14, 56) ms min�1]
than in the patients with PIH [7 (6, 18) ms min�1] (P< 0.01,
Mann–Whitney U-test).
The relationship between PTT and MAP was examined
before and after spinal anaesthesia (Fig. 2). There was a
Table 2 Patient details and cardiovascular measurements before and after spinal anaesthesia. Values are median (interquartile values). ns, not significant. Student’s
t-test, *P<0.05, **P<0.0001; Mann–Whitney U-test, #P<0.01
Normotensive subjects Pregnancy-induced hypertension Significance
Patient details
Number 58 15
Age 32 (30, 35) 32 (30, 37)
Height (cm) 162 (158, 168) 162 (160, 170)
Weight (kg) 70 (61, 78) 72 (62, 83)
Gestation (weeks) 39 (39, 39) 36 (33, 38)
Cardiovascular values
Before spinal anaesthesia
Heart rate (beats min�1) 89 (78, 102) 80 (74, 94) *
Arterial pressure (mm Hg)
Mean 99 (91, 104) 115 (104, 119) **
Systolic 126 (118, 138) 144 (138, 160) **
Pulse transit time (ms) 390 (345, 422) 353 (325, 399) *
After spinal anaesthesia
Heart rate (beats min�1) 87 (78, 109) 80 (71, 101) ns
Arterial pressure (mm Hg)
Mean 92 (86, 99) 106 (98, 111) **
Systolic 124 (116, 136) 140 (136, 154) ns
Pulse transit time (ms) 413 (373, 454) 370 (342, 417) *
Measurements at greatest pulse transit time or first intervention
Heart rate (beats min�1) 96 (78, 109) 79 (75, 98) ns
Mean arterial pressure (mm Hg) 77 (66, 90) 89 (98, 111) **
Change in mean arterial pressure 18 (5, 33) 22 (11, 29) ns
Systolic arterial pressure (mm Hg) 106 (92, 120) 119 (111, 134) ns
Pulse transit time (ms) 488 (429, 532) 417 (389, 495) *
Greatest change in PTT (ms) 94 (62, 123) 75 (54, 118) ns
Greatest change in PTT (%) 24% 21% ns
Rate of change in PTT (ms min�1) 32 (14, 56) 7 (6, 18) #
Time to greatest PTT change (min) 2.4 (1.4, 3.4) 5.0 (3.2, 7.7) #
Minimum arterial pressure after spinal anaesthesia
Mean 69 (60, 78) 83 (78, 95) **
Systolic 97 (87, 108) 116 (108, 126) **
700
600
500
400
300150
100
50
0
200
100
010 15 20
Time (min)
PT
T (
ms)
and
hea
rt r
ate
(bea
ts m
in–1
)
Arterial pressure (m
m H
g)
25 30
Spinal
Sitting
Doses of ephedrine 6 mgDoses of atropineDoses of phenylephrine
Fig 1 An example of patient responses. Upper, continuous trace: pulse
transit time (ms). Lower, discontinuous trace: heart rate calculated from
successive R-R intervals. Systolic and diastolic arterial pressures are shown
as vertical bars and arrowheads.
Sharwood-Smith et al.
102
Thesis page 68
significant correlation in both the normotensive (r2=0.55,
P<0.0001) and the PIH group (r2=0.45, P<0.0001)
(Fig. 3). The slopes of the relationships between PTT and
MAP were not different when normotensive and hypertens-
ive subjects were compared [slopes (95% confidence inter-
val, CI) were �3.12 (�3.64, �2.59) and �2.88 (�4.12,
�1.64) ms (mm Hg)�1 respectively].
We examined the sensitivity and specificity of changes in
PTT to indicate the onset of hypotension. The resulting
receiver operating characteristic (ROC) curves for decreases
in MAP of 5 and 10% are given in Figure 4. For a decrease in
MAP of 5%, an increase of 10% in PTT was 95% sensitive
but only 15% specific. If a cut-off value of a 20% increase in
PTT was taken, the sensitivity and specificity were 69 and
77% respectively. The area under the ROC curve was 0.79
(95% CI, 0.68–0.9; P<0.001 compared with an area of 0.5).
Considering decreases in MAP of more than 10%, an
increase of 20% in PTT was 74% sensitive and 70% specific.
The area under the ROC curve was 0.72 (95% CI, 0.60–0.85;
P<0.001 compared with an area of 0.5).
Discussion
To our knowledge, the relationship between PTT and arterial
pressure has not previously been studied systematically
during obstetric spinal anaesthesia. We chose to study
this scenario because rapid and substantial changes in arter-
ial pressure are relatively frequent. We found that changes in
PTT were related to arterial pressure changes and that the
relationship between PTT and arterial pressure was the same
in normotensive patients and those with PIH.
We measured the time interval between the ECG R wave
and the upsweep of the plethysmograph.11 12 This time
includes two principal components, the time between elec-
trical activation of the ventricle and cardiac ejection, and the
50
800A
B
600
400
200100
Mean arterial pressure (mm Hg)
PT
T (
ms)
PT
T (
ms)
150
50
800
600
400
200100
Mean arterial pressure (mm Hg)150
Fig 2 Relationship of pulse transit time to mean arterial pressure in (A)
normotensive subjects and (B) patients with pregnancy-induced hyperten-
sion. The open symbols are before and the closed symbols after spinal
anaesthesia. The linear regression relationships are shown with the 95%
confidence interval for the line. Both relationships are significant
(P<0.0001).
550
450
Pul
se tr
ansi
t tim
e (m
s)
350
250
50 60 70 80 90
Mean arterial pressure (mm Hg)
100 110 120 130 140
Normotensive patientsPIH patients
Fig 3 Comparison of the linear regression relationships of pulse transit time
and mean arterial pressure in normotensive subjects and patients with
pregnancy-induced hypertension. The outer lines represent the 95% con-
fidence interval for the regression.
0
100
80
60
40
20
020 40 60
1-Specificity (%)
Sen
sitiv
ity (
%)
80 100
5% decrease in mean arterial pressure10% decrease in mean arterial pressure
Fig 4 Receiver operating characteristic curves for changes in pulse transit
time in relation to a decrease in mean arterial pressure by 5 and 10%. For the
5% decrease, the area under the curve is 0.79 (0.68–0.90) and for the 10%
decrease the area is 0.73 (0.60–0.85) (95% confidence intervals) Both areas
are significantly greater than 0.5 (P<0.001).
Pulse transit time during obstetric spinal anaesthesia
103
Thesis page 69
time taken for the resultant pressure wave to be transmitted
along the artery to generate the plethysmograph upstroke.11
The time from ventricular activation to cardiac ejection
depends upon a number of factors related to preload,
heart rate and contractility.13 14 This time is small compared
with the time taken for pulse wave transmission along the
vessel, particularly in young normotensive patients.
Consequently, the greater part of the PTT we measured
indicates vascular elastance according to the Bramwell–
Hill relationship15 described for the velocity of pressure
waves:
Velocity ¼ffiffiffiffiffiffiffiffiffiffiffiffiffiffiffiffiffiffiffiffiffiffiffiffiffiffiffiffiffiffiffiffiffiðDP=½V=DV�·rÞ
p
where r is the density of blood and DP/[V/DV] is the
specific elastance of the vessel. The pressure–volume
relationship of arteries is non-linear: as pressure decreases,
elastance decreases, pulse wave velocity decreases and PTT
is increased, as we have confirmed. Other factors that affect
vascular elastance, such as hypertension and change in
sympathetic activation, could also affect PTT, but these
influences are disputed. For example, although ultrasound
estimates of radial artery elastance suggest that arterial
infusion of phenylephrine can increase elastance,16 others
have concluded that greater arterial elastance in hypertens-
ive patients can be explained entirely by differences in
arterial pressure.7 17 These findings are supported by the
present study, in which we found no discernible difference
between normotensive patients and those with PIH in the
relationship for arterial pressure and PTT. We conclude
that the mechanical properties of the large conducting
vessels in patients with this condition are not affected,
whereas the resistance vessels are clearly affected. This
finding is not altogether unexpected: the site of modula-
tion of arterial resistance depends upon the type of
stimulus.18
The shape of the pressure waveform in peripheral arteries
varies considerably with age and disease.19 The rate of
increase of the pressure varies considerably with age, but
in the limited range of ages that we studied this could not
cause much variation.
There is a difference in time between the occurrence of
plethysmograph waveforms in the finger and toe because of
differences in distance along the arteries. Epidural anaes-
thesia increases this time difference and was attributed by
the investigators to sympathetic blockade in the leg arter-
ies.21 However, the time difference only increased between
10 and 20% and this increase was accompanied by a
decrease in arterial pressure. Consequently, an equally
plausible alternative explanation is that hypotension, caus-
ing a proportional increase in pulse wave transmission time,
would have a greater absolute effect in the longer vessel.
This effect can account for the changes reported by these
workers.
Recently, marked changes in PTT were described during
general anaesthesia in association with tracheal intubation,
and these changes were attributed to autonomic activation.4
However, no measurements of arterial pressure were repor-
ted. Once again, the changes could have been caused by
changes in arterial pressure, because the hypertensive
response to insertion of the tracheal tube will increase arter-
ial elastance and reduce PTT, as the authors reported.
Monitoring by means of PTT has been compared with
invasive arterial pressure measurements. If the directly
measured pressure changed by more than 10 mm Hg,
then PTT accurately tracked the change on 67% of occa-
sions. However, the authors of this study concluded that PTT
did not have sufficient accuracy to replace direct arterial
measurements.22
Clinically, PTT changes are of interest as a non-invasive
beat-to-beat index of arterial pressure changes. Increased
arterial pressure itself causes increased arterial stiffness
but the relationship is non-linear at high and low pressures.23
In the present study, by using a large control group, in which
there were considerable changes in PTT, we found a cor-
relation between MAP and PTT changes. More than 50% of
the variance in PTT is explained by the value of the MAP.
The remainder of the variance must result from other factors,
such as patient size, variation in accuracy of estimates of
both arterial pressure and PTT, and individual variations in
vessel wall characteristics. Arterial behaviour can be altered
by obesity,24 longitudinal tension25 and vasoactive mediat-
Sharwood-Smith et al.Thesis page 70
The analogue device that we used detected the maximum
rate of change of the plethysmograph waveform. In prelim-
inary unpublished studies of healthy volunteers, we used a
method of intersecting tangents to determine the nadir of the
plethysmograph waveform. Measurements of PTT using this
nadir were less affected by changes in heart rate than meas-
urements made using the time to the maximum rate of
change of the plethysmograph signal. These findings con-
firm those of others.20 However, this method was not com-
patible with analogue preprocessing, in that we not could
detect the maximum rate of change of the plethysmograph
wave. It was therefore not practical for this study. Thus, one
source of variation in the relationship between PTT and
arterial pressure could result from heart rate changes and
the method used by our analogue detector.
ors.16 Although these additional factors increase the vari-
ation between subjects, it is likely that they will not influence
the variation within an individual, so PTT can be a useful
measure of moment-to-moment changes within a particular
patient.
Our results were obtained in pregnant subjects, and the
mechanical properties of large vessels such as the aorta can
be affected by hormonal changes such as may occur in
pregnancy.26 However, the vascular changes of PIH are
probably confined to small resistance vessels,27 28 explaining
the similar relationship between PTT and arterial pressure in
normotensive and PIH patients.
Non-invasive methods for arterial pressure measurement,
such as automated sphygmomanometers, frequently fail to
display values when patient movement causes interference.
104
This is a particular problem in obstetric anaesthesia, where
the subjects are awake and may be agitated and the proced-
ures are often urgent, with little opportunity for careful cuff
application and even less for arterial cannulation. We found
that PTT could potentially be used, in these circumstances,
to predict the onset of hypotension. The sensitivity and spe-
cificity are sufficient to indicate instantaneously changes in
arterial pressure and provide a rapid, non-invasive, within-
subject indication of hypotension. This may be of consid-
erable value if invasive monitoring is not justified. We found
no evidence that the properties of large arteries are affected
by PIH.
AcknowledgementsWe thank Professor A. Dahan, University of Leiden, for the loan of theanalogue computer for processing the ECG and optical plethysmographsignals (Ajax). This study was supported by a grant from the ObstetricAnaesthetists Association.
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appraisal of potential clinical applications. Thorax 1999; 54:
452–82 Weiss T, Del Bo A, Reichek N, Engelman K. Pulse transit time
in the analysis of autonomic nervous system effects on thecardiovascular-system. Psychophysiology 1980; 17: 202–7
3 Sawada Y, Yamakoshi K. A correlation analysis between pulsetransit time and instantaneous blood pressure measured indir-
ectly by the vascular unloading method. Biol Psychol 1985; 21: 1–94 Singham S, Voss L, Barnard J, Sleigh J. Nociceptive and anaesthetic-
induced changes in pulse transit time during general anaesthesia.Br J Anaesth 2003; 91: 662–6
5 Landowne M. A method using induced waves to study pressurepropagation in human arteries. Circ Res 1957; 5: 594–601
6 Bramwell JD, Downing AC, Hill AV. The effect of blood pressureon the extensibility of the human artery. Heart 1923; 10: 289–95
7 Gribbin B, Pickering TG, Sleight P. Arterial distensibility in normaland hypertensive man. Clin Sci 1979; 56: 413–7
8 Schulze-Bauer CAJ, Holzapfel GA. Determination of constitutiveequations for human arteries from clinical data. J Biomech 2003;
36: 165–99 Clark VA, Sharwood-Smith GH, Stewart AVG. Ephedrine
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10 Davey DA, MacGillivray I. The classification and definition of thehypertensive disorders of pregnancy. Am J Obstet Gynecol 1988;
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12 Bugram R, Akhlaghi-Farsi H, Maresch H, Pfurtscheller G. Amethod for determining pulse transmission time. Biomed Tech
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Am Heart J 1961; 62: 367–7415 Bramwell JC, Hill AV. The velocity of the pulse wave in man. Proc R
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of radial artery compliance in congestive heart failure. Hyperten-sion 1995; 26: 348–54
17 Laurent S. Arterial wall hypertrophy and stiffness in essentialhypertensive patients. Hypertension 1995; 26: 355–62
18 Folkow B, Sonnenschein RR, Wright DL. Loci of neurogenic andmetabolic effects on precapillary vessels of skeletal muscle.
Acta Physiol Scand 1971; 81: 459–71
19 McLean CE, Clason WPC, Stoughton PV. The peripheral pulse asa diagnostic tool. Angiology 1964; 14: 221–31
20 Chiu YC, Arand PW, Shroff SG, Feldman T, Carroll JD. Deter-mination of pulse-wave velocities with computerized algorithms.
Am Heart J 1991; 121: 1460–7021 Babchenko A, Davidson E, Adler D, Ginosar Y, Kurz V, Nitzan M.
Increase in pulse transit time to the foot after epidural anaesthesiatreatment. Med Biol Eng Comput 2000; 38: 674–9
22 Young CC, Mark JB, White W, DeBree A, Vender JS, Fleming A.Clinical evaluation of continuous noninvasive blood pressure
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23 Schulze-Bauer CAJ, Holzapfel GA. Determination of constitutiveequations for human arteries from clinical data. J Biomech 2003;
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25 Wang YY, Jan MY, Wang GC, Bau JG, Wang WK. Pressure pulsevelocity is related to the longitudinal elastic properties of the
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Pulse transit time during obstetric spinal anaesthesia
105
Thesis page 71
“I would have everie man write what he knowes and no more.”–Montaigne
BRITISH JOURNAL OF ANAESTHESIA
Volume 102, Number 3, March 2009
British Journal of Anaesthesia 102 (3): 291–4 (2009)
doi:10.1093/bja/aep003
Editorial I
Hypotension in obstetric spinal anaesthesia: a lesson from pre-eclampsia
Vasopressor use to prevent hypotension occurs after 80%
of spinal anaesthetics for Caesarean section.1 The problem
was first recognized 50 yr ago2 when it was attributed to
caval compression. This theory became accepted as the
basis for clinical management, and it remains current
today.3 4 However, using this theory as a basis for the
management of hypotension has proved disappointingly
ineffective.5 6 Important information from the ‘natural
experiment’ of pre-eclampsia was overlooked, and fresh
information from vascular biology now calls for a reconsi-
deration of our management of hypotension in these
circumstances.
Previously, the concept of compression of the vena cava
and the aorta was linked to three features, which can
coexist and are often considered together. However, each
probably has a different mechanism. First, spinal anaesthe-
sia almost always causes hypotension in normal preg-
nancy, and we will consider the reasons for this
phenomenon later. Secondly, cardiac output can be
reduced by aortocaval compression when some mothers lie
in the supine position, although this is not necessarily
clinically evident. Thirdly, a marked bradycardia with a
reduction in cardiac output and severe hypotension can
occur suddenly in a few subjects at some time after the
mother moves to the supine position. This reflex effect is
the relatively uncommon supine hypotensive syndrome of
pregnancy (SHSP).7
Holmes8 proposed that compression of the inferior vena
cava by the gravid uterus caused hypotension after spinal
anaesthesia because venous return was reduced and thus
cardiac output decreased. Marx9 developed the concept
that blood was trapped in the legs, and introduced the
treatment strategy of ‘acute hydration’ supported by a
widely cited illustrative case history. Subsequently, fluid
administration before spinal anaesthesia became the puta-
tive ‘prophylaxis’ and an almost universal therapy.10
The theory of caval compression and supine hypotension
was based largely on studies by Scott and colleagues,11
who measured cardiac output by dye dilution in eight
patients. Overall, cardiac output was 12% less in the supine
compared with the lateral position. In three subjects, the
mean reduction was only 6% and the investigators
suggested that vena caval compression was relieved
because the fetal head was engaged.11 However, in two
patients, there was sudden bradycardia, hypotension, and a
decrease in cardiac output by more than 50%, suggesting a
reflex response. Clearly, this study reported a heterogeneous
group of patients, and the patients with bradycardia devel-
oped the supine hypotensive syndrome, which is a different
phenomenon from the hypotension seen in the other
patients in that study. An extensive review of SHSP found a
wide range of case selection, clinical features, definitions,
and degrees of hypotension.12 Severe hypotension was
reported in 2.5–20% of these patients. In some patients,
hypotension only occurred after 20 min in the supine pos-
ition. The possible reasons given for hypotension in these
patients were either vena caval obstruction or a vagal reflex
bradycardia, which is a well-known phenomenon associated
with poorly filled heart.13 Later studies found much less
difference between supine and lateral positions. Using
transcutaneous Doppler, a maximum change of cardiac
output of 6% occurred with moving from supine to a left
158 tilt, and fetal head engagement made no difference.14
Undoubtedly, the vena cava is affected by the gravid
uterus. Femoral venous and distal inferior caval pressures
were greater in the supine position. In the lateral position,
venous pressure was less, but still not as low as non-
pregnant levels.15 Angiography showed occlusion of the
inferior vena cava and distension of the collateral azygos
circulation in 12 supine patients having Caesarean section
under general anaesthesia. The abdominal vena cava
remained partly occluded in the lateral position.16
However, in these studies, the link between changes in
venous behaviour and hypotension was inferred rather than
directly proved. No early studies involved spinal anaesthe-
sia because general anaesthesia and increasingly epidural
anaesthesia had, by that time, largely replaced spinals for
Caesarean section in the UK.
# The Board of Management and Trustees of the British Journal of Anaesthesia 2009. All rights reserved. For Permissions, please e-mail: [email protected]
Thesis page 72
Digital thesis publication by permission of Oxford University Press 2011
The proponents of the caval compression theory
suggested three ways to prevent hypotension after spinal
block, but none has withstood careful examination. First,
infusion of crystalloid or colloid was proposed to compen-
sate for the venous blood said to be trapped in the legs,
but initial reports of success in preventing hypotension17
were not replicated in subsequent studies.1 5 6 Colloid
administration could increase cardiac output transiently,
perhaps by haemodilution and reduced viscosity, but this
effect was not sustained after sympathetic block with a
spinal. Secondly, leg compression was attempted but was
relatively ineffective, despite the success of the anti-G suit
in preventing lower limb pooling and hypotension in aero-
space medicine.18 Finally, the tilt manoeuvre was advo-
cated to reduce caval occlusion. Although widely used,
this procedure is variably applied,19 and does not prevent
hypotension after spinal anaesthesia.6 There is no escape
from the fact that therapies based on the concept of caval
compression do not reliably prevent hypotension after
spinal anaesthesia in Caesarean section. Despite this,
current books suggest routine use of strategies based on
these putative explanations,4 and current teaching uses
these concepts.
The original hypothesis underlying the mechanism of
hypotension was that a reduction in central venous
pressure would reduce cardiac output, and thus reduce
arterial pressure. This concept should be reconsidered. The
hypothesis was based on the view that central venous
pressure controls cardiac output, as suggested by the
experimental studies of Paterson and Starling20 and
Guyton.21 A clear understanding of the limits of Starling’s
studies is vital. They were of an isolated heart, supplied
with blood from a venous chamber which could be raised
or lowered to adjust the atrial pressure. In this ‘open’
system, output was not related to supply. The supply to the
venous reservoir was externally adjusted by the investi-
gator to keep the atrial pressure constant. By raising the
reservoir to increase inflow pressure, the stretch of the ven-
tricular muscle was increased, and thus ejection volume
increased. To maintain the atrial pressure, the atrial reser-
voir had to be replenished more rapidly. In these circum-
stances, atrial pressure regulated cardiac output. This did
not mean that the increased flow from the venous reservoir
had increased the cardiac output, only that the flow had to
be increased to sustain the reservoir pressure. The entirely
separate studies of Guyton in which he related atrial
pressure and venous return were equally artificial. Venous
return was controlled using an adjustable pump. When the
pump rate and thus the experimentally controlled ‘venous
return’ was increased, a limit was reached where a
decrease in venous pressure occurred and venous return
did not change, implying upstream flow limitation.21 In
the whole body, the two factors of venous return and
cardiac output are of course linked, in the long term, and
neither is the ‘cause’ or ‘effect’ of changes in output or
venous pressure, merely two sides of the same coin. The
inextricable link between venous return and cardiac
output, and the unrealistic question concerning which is
the cause and which is the effect, was recognized by
Guyton, despite his considering venous pressure to be an
independent variable. Even at the time, this highly artifi-
cial experiment was recognized as unlikely to be appli-
cable to the intact animal.22 In recent years, the
relationship between venous pressure and cardiac output
has been re-evaluated23 24 and this has led to robust con-
troversy.25 26 Reddi and Carpenter27 repeated previous sug-
gestions23 25 that it makes more sense to re-draw the
Guyton plot with cardiac output on the abscissa (Fig. 1),
to escape the common misconception that a decrease in
right atrial pressure would act to increase blood flow
through the veins. The important feature of the venous
system is its compliance, not its resistance, and we can
relate the central venous pressure to the volume held in
the veins.28 A recent helpful view is that the volume in the
venous system is more relevant than the pressure, and that
‘Venous Excess’ is the important regulating factor on the
venous side of the circulation.27 Venous capacitance and
its regulation in pregnancy may be an important element
in understanding the haemodynamic response to spinal
anaesthesia. For example, the splanchnic component of
this capacitance drains directly into the vena cava via the
hepatic vein which is not directly compressed by the
uterus. However, we lack basic information on these
aspects of venous dynamics.
The sensors that normally control arterial pressure, in
the carotid sinus and the aorta, lie on the arterial side of
the circulation, and are the sensors of the baroreflex. Why
does this reflex fail to maintain arterial pressure after
Cardiac output
Right atrial pressure
Rig
ht a
tria
l pre
ssur
e
Venousreturn curve
Cardiacfunction Cardiac
function
A B Venousreturn curve
Original Starling’s relationship.The cardiac function curvesuggests that right atrial pressurecontrols cardiac output
Venous return curveThe heart acts as a ‘Sump pump’and affects atrial pressure as itsoutput is regulated.21
Venous return
Cardiac outputVenous return
Fig 1 Comparison of cardiac function and venous return curves. (A)
Cardiac function curve, after Guyton.19 This relationship is based on the
function of the isolated heart. An increase in central venous pressure
causes an increase in cardiac output. The dependent variable (cardiac
output) is plotted on the y-axis. (B) Venous return curve (also termed
systemic or vascular function) which is the relationship found when the
venous return is modified as the independent variable: under these
circumstances, an increase in venous return reduces right atrial pressure.21
Combining the two curves on one diagram condemns one of the
relationships to have an independent variable expressed on the y-axis.
292
Editorial IThesis page 73
spinal anaesthesia in pregnancy? Part of the answer to this
question can be found in the pathophysiology of pre-
eclampsia. Remarkably, studies done in the 1950s showed
that pregnant women with toxaemia (severe pre-eclampsia)
were far less likely to develop hypotension after spinal
anaesthesia than normal pregnant or non-pregnant women.
Similar differences were seen in response to autonomic
ganglionic block, supporting the conclusion that withdra-
wal of sympathetic activity had less effect in the patient
with pre-eclampsia.29 30 For some reason, these studies
were downplayed, although the proponents of the caval
compression theory knew of them.2 More recent studies
corroborate the ability of pre-eclamptic patients to sustain
arterial pressure after the spinal block.31
In pre-eclampsia, vascular epithelium is damaged by a
process involving placental-derived proteins, leading to
an imbalance between pro- and anti-angiogenic growth
factors,32 33 which results in persistent vasoconstriction.
In contrast, the normal pregnant patient is very sensitive
to spinal anaesthesia, because of an altered balance of
vascular tone. Responses to endogenous pressors, par-
ticularly angiotensin II, are reduced. This is caused by
an endothelium-dependent alteration of vascular smooth
muscle function. Additionally, there is increased syn-
thesis of vasodilator prostaglandins and nitric oxide.
These effects increase dependence on sympathetic vascu-
lar tone in normal pregnancy.34 35 The use of sympatho-
mimetic vasopressors to sustain arteriolar tone and thus
arterial pressure has become the most important strategy
for safe spinal anaesthesia in contemporary practice,
despite the prevailing theory of caval occlusion being
responsible for hypotension after a spinal in normal
pregnancy. Indeed, those who suggested that caval com-
pression caused circulatory disturbances had advised
against pressor agents to treat hypotension, suggesting
that they would cause vasoconstriction but would not
improve venous return.16
Nevertheless, aortocaval compression can reduce
cardiac output and impair placental blood flow, so it
remains rational to use tilt during anaesthesia, although
the exact contribution of tilt to reducing hypotension in
spinal anaesthesia is unclear.
After 40 yr, the relationship between spinal anaesthe-
sia, pre-eclampsia, and hypotension can be properly
acknowledged and put into clinical practice. These obser-
vations shed light on the circulatory effects of spinal
anaesthesia in normal pregnancy. Research in obstetric
anaesthesia can now move on from the legacy of an
uncertain hypothesis by learning the lessons of pre-
eclampsia and understanding how the features of this
disorder illuminate our current concepts. Modern non-
invasive methods such as ultrasound, MRI, and measures
of skin blood flow36 should be used in pregnancy to
explain the effects of spinal anaesthesia more exactly.
Better management and training based on logical theories
should follow.
G. Sharwood-Smith and G. B. Drummond*
Department of Anaesthesia, Critical Care, and Pain
Medicine
Royal Infirmary
Edinburgh EH16 4HA
UK
*E-mail: [email protected]
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